Review Article Emerging Roles of Focal Adhesion Kinase in ...BioMed Research International Cyclin D 1 Cyclin E Mdm 2-p 53 p21 p27 Cas-Rac IAPs MEK-ERK 1/2 NF- B PI 3K-AKT RIP SMAD

Review ArticleEmerging Roles of Focal Adhesion Kinase in Cancer

Yu-Ling Tai1 Lih-Chyang Chen2 and Tang-Long Shen13

1Department of Plant Pathology and Microbiology National Taiwan University Taipei 10617 Taiwan2Department of Medicine Mackay Medical College New Taipei City 25245 Taiwan3Center for Biotechnology National Taiwan University Taipei 10617 Taiwan

Correspondence should be addressed to Tang-Long Shen shentlntuedutw

Received 16 January 2015 Accepted 20 February 2015

Academic Editor Hiroshi Hasegawa

Copyright copy 2015 Yu-Ling Tai et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Focal adhesion kinase (FAK) is a cytoplasmic nonreceptor tyrosine kinase that enables activation by growth factor receptors orintegrins in various types of human cancersThe kinase-dependent and kinase-independent scaffolding functions of FAKmodulatethe authentic signaling and fundamental functions not only in cancer cells but also in tumor microenvironment to facilitate cancerprogression andmetastasisThe overexpression and activation of FAK are usually investigated in primary or metastatic cancers andcorrelated with the poor clinical outcome highlighting FAK as a potential prognostic marker and anticancer target Small moleculeinhibitors targeting FAK kinase activity or FAK-scaffolding functions impair cancer development in preclinical or clinical trials Inthis review we give an overview for FAK signaling in cancer cells as well as tumor microenvironment that provides new strategiesfor the invention of cancer development and malignancy

1 Introduction

Cancer signaling emanated from the interaction betweencancer cells and tumor microenvironment is critical forcancer development Integrins are essential bidirectionaltransmitters in regulating the physical link and signal com-munication between the inside and the outside of the plasmamembrane Upon integrins engagement with extracellularmatrices (ECMs) integrins cluster together on the plasmamembrane to ensure the efficient recruitment and activationof various molecules such as adaptor proteins (eg p130Casand Crk) nonreceptor tyrosine kinase (ie Src family kinaseand focal adhesion kinase) small GTPases (eg Rho Racand Cdc42) and cytoskeletal proteins (eg talin vinculinand paxillin) by forming intracellular specialized complexesand structures named as focal adhesions (or focal contacts)[1] Utilizing varied signaling proteins within focal adhe-sions integrin-mediated signaling enables transmitting celladhesion signaling as well as tuning the reorganization ofcytoskeleton important for tumor progression such as tumorangiogenesis and metastasis

In response to cell adhesion activation of focal adhesionkinase (FAK) is prominent followed by initially recruited

to focal contacts and subsequently autophosphorylated onits Tyr397 to participate in integrin-mediated signaling andfunctions [2ndash4]The FAKnonreceptor tyrosine kinase bears acentral kinase domain flanked by anN-terminal FERM (band41 and ezrinradixinmoesin homology domain) domainand a C-terminal region containing a FAT (focal adhesiontargeting) domain and several proline-rich motifs [5] whichallows transducing extracellular signals through tyrosinephosphorylation onto a diverse of intracellular molecules inthe interior of a cell in both adhesion-dependent and growthfactor dependent manners Specifically in line of integrinactivation the FAT domain of FAK enables targets FAK ontofocal adhesion sites via interactions with other focal adhesioncomplex proteins such as paxillin vinculin and talin Con-sistent with this scenario we have deciphered an inhibitorymechanism of FAK activation in which the intramolecularinteraction between the FERM and kinase domains confersFAK toward an inactive conformation and the release ofthis autoinhibition rendered by upstream integrin signaling(ie cell adhesion) andor growth factor signaling in aproximal fashion allows the kinase domain of FAK accessibleto numerous catalytic substrates essential for its activa-tion and downstream signaling events [6ndash8] Subsequently

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 690690 13 pageshttpdxdoiorg1011552015690690

2 BioMed Research International

the autophosphorylation of FAK on Tyr397 creates a high-affinity binding site for Src homology 2 (SH2) domain-con-taining proteins such as Src family kinases phosphoinositide3-kinase phospholipaseC and growth factor receptor-boundprotein 7 (Grb7) [9ndash12] thereby relying the upstream signalon versatile downstream signaling pathways Moreover thebinding of Src family kinases onto the phospho-Tyr397 ofFAK contributes to the promotion of FAK kinase activity andsignaling as a result of additional tyrosine phosphorylationson several tyrosine sites including Tyr407 Tyr576 Tyr577andTyr925 of FAK [5] In fact the phosphorylation of FAKonTyr576 and Tyr577 by Src leads to a steric effect on preventingan intramolecular interaction between the aminoterminalFERM domain and the kinase domain within FAK [13] Onthe other hand phospho-Tyr925 of FAK provides a dockingsite for growth factor receptor-bound protein 2 (Grb2)leading to activation of a RAS-MEKERK cascade [14 15]In addition the scaffolding functionality of FAK through itsphospho-tyrosine sites and two proline-rich motifs (mainlylocatedwithinC-terminus) has been observed and elaboratedin attribution with targeting a certain array of signalingproteins to focal adhesion sties in response to specific integrinactivation [16] Given the sophisticated regulated mechanismof FAK activation and signal transmission a myriad ofcellular and pathophysiological functions enable modulatedin a coopted manner stemming from integrin andor growthfactor activation Indeed via recruiting and phosphorylatingnumerous signaling proteins FAK empowers cell migrationand modulates cell proliferation adhesion apoptosis anddifferentiation in response to cell adhesion and mitogenstimulation [5 17] implicating in controlling a wide range ofprocesses of tumor [17] Inevitably the mechanistic nature ofFAK activation and signaling has been intensively studied tohighlight it as a potential target for anticancer therapeutics

Tumor microenvironment a mixture of varied cell typesas well as secreted cytokines and deposited ECMs is indis-pensable for tumor progression and metastasis [18 19]Upregulation of integrins and FAK is often observed to cor-relate with the progression of tumor development implyingthe integrinFAK signaling involved in regulation of tumordevelopment [20] Moreover the activation of FAK enablesmodulation by growth factor stimulation In this review weprovide an overview of FAK signaling in cancer cell biologyand discuss how FAK signal transduction controls the cancerdevelopment and progression as summarized in Figure 1 Inaddition we also summarize the potent anticancer drugs inrelation to FAK-mediated signaling

2 FAK in Cancer Cells

21 FAK Signaling in Cancer Cell Survival and Proliferation

211 FAK Regulates Cancer Survival FAK-mediated signal-ing plays a critical role in the regulation of cancer cell survivalIn opposite to cell adhesion anoikis is a form of programmedcell death due to the disruption of cell-ECM interactionsin which FAK activity is lost and therefore results in cellapoptosis [21 22] In contrast often overexpression of FAK

in cancer cells seems to attribute the resistance of celldetachment-induced cell death (ie anoiksis) Indeed inthese cancer cells the increased FAKSrc complex confers theactivation of both PI3K-AKT and MEK-extracellular signal-regulated kinase 12 (ERK12) signal transductions therebyenhancing the ability of cancer cell survival and growth ina cell detached condition [23] In addition several otherupstream signals also contribute to FAK-mediated anoikisresistance in cancer cells For example transforming growthfactor-120573 (TGF-120573) induces the activation of FAK and AKTvia SMAD3 and p38 MAPK respectively which in turnresults in anoikis resistance and tumor promotion [24]In squamous cell carcinoma (SCC) fibronectin-mediatedintegrin 120572V activation leading to FAK phosphorylation atTyr397 prevents suspension-induced or tumor suppressorp53-mediated anoikis [25] As expected disruption of theorganized fibronectin structure enables anoikis of SCCpresumably losing FAK phosphorylation and ERK activationMoreover overexpression of FAK has been shown to blockthe caspase-3-mediated apoptosis conversely inhibition ofFAK leads to apoptosis in cancer cells [26] Hence knock-down of FAK expression by RNA interference promotesanoikis and further inhibits pancreatic cancer metastasis invivo [27]

Antiapoptotic property is also essential for FAK in pre-vention of cancer programmed cell death Actually overex-pression of FAK apparently links to the activation of PI3K-AKT signal transduction and promotes the expression of NF-120581B-mediated inhibitor-of-apoptosis proteins (IAPs) whichwarrants apoptotic inhibition by blocking caspase-3 cascadein human leukemia [28] Likewise the phosphorylation ofNF-120581B and activation of PI3KAKT signaling modulated byFAK disable the tumor necrosis factor-120572- (TNF-120572-) inducedapoptosis [29] Moreover FAK also reportedly binds to thedeath domain kinase receptor-interacting protein (RIP) acomponent of death receptor complex in the programmedcell death by which FAK is capable of suppressing apoptosisby blocking the function of death domain of RIP [30] Thesestudies indicate that an essential role for FAK activation andFAK-mediated signal transduction is to direct the fate ofcancer cells by preventing the programmed cell death

212 FAK Regulates Cancer Proliferation Cell proliferationis a process of the increment of cell number as a result ofcell division and growth Discovery of the expression andtyrosine phosphorylation of FAK highly correlated with cellcycle progression by modulating cell cycle-relative molecules[31] highlights FAK functioning as a key regulator in pro-moting cancer proliferation Eventually overexpression ofFAK enables increasing cyclin D1 expression and decreasingcyclin-dependent kinase (CDK) inhibitor p21 expressionthereby accelerating G1 to S-phase transition Conversely thecompetition of FAK localization and function out from focalcontacts by a dominant-negative FAK mutant inhibits cellcycle progression at G1 phase [32] Furthermore FAK hasbeen elaborated to modulate the E26 transformation-specific(ETS) binding site resided within the cyclin D1 promoterwhich in turn regulates the transcriptional activation of

BioMed Research International 3

Cyclin D1

Cyclin EMdm2-p53

p21p27

Cas-Rac

IAPsMEK-ERK12

NF-120581BPI3K-AKT

RIPSMAD3

Grb7 and PI3KJNK-paxillin

p190RhoGEF-RhoERK2-Calpain 2

Cas-Crk

Cas-Crk-Dock180-ELMOmiR-18a

Rac1-JNK-MMPsE-cadherin

PI3KAngiopoietin-1

-SMA

Endophilin A2

TGF- and cytokines

PI3K

LOXL2

N-WASP-Cdc42-Arp23

Extracellular matrix

Integrins Growth factorreceptors

MigrationSproutingAngiogenesis

Growth factor


IntegrinsGrowth factor receptors

FAK

Src

AKT

Cancer stem cell

ProliferationInvasion

Growth factor

Cancer-associated fibroblast

FAK

macrophageTumor-associated

FAKSrc

Cancer cell development

ProliferationSurvivalMigration Invasion and metastasis

Endothelial cell

FAK AKT

FAK

AKT

ERKJNK

Antiapoptosis120572

120573

Figure 1 Model for FAK signal transduction in cancer cells and tumor microenvironment The activation of FAK principally initiatedby integrin engaged with ECMs and also by growth factor receptors enables regulating cell survival proliferation migration invasionand metastasis in relation to cancer development Subsequently the autophosphorylated (on Tyr397) FAKSrc complex empowers tyrosinephosphorylation cascades in modulating versatile signal pathways For example FAK modulates endophilin A2 phosphorylation by Srcor PI3K-AKT signaling in cancer stem cells In endothelial cells vascular endothelial growth factor-A (VEGF-A)VEGF or angiopoietin-1 signalling regulates FAK-mediated PI3KAKT activation to promote migration sprouting and angiogenesis FAK also regulates theexpression of growth factors or cytokines in tumor-associatedmacrophages to facilitate cancer progression In response to LOXL2 stimulationFAK affects the 120572-SMA expression and AKT signaling to control invasion antiapoptosis and proliferation in cancer-associated fibroblasts

cyclin D1 and leads to promoting cell cycle progression [33]Indeed overexpression of FAK also exits cell cycle from G1phase in glioblastoma Consistently the promotion of cellcycle progression by FAK ismediated by enhanced expressionof cyclin D1 and cyclin E in concert with reduced expressionof CDK inhibitors p27Kip1 and p21Waf1 [34]

The tumor suppressor p53 triggers lots of antiproliferativeprocesses such as DNA repair apoptosis and cell cycle arrest[35] On the other hand FAK promotes cell cycle progressionby the blockage of tumor suppressor p53-mediated apop-tosis and the inhibition of p53 transcriptional activity [36]Mechanically it has been proposed that FAK might exert itsFERM domain as a scaffold to stabilize p53 and ubiquitinE3-ligases Mdm2 in the nucleus which in turn enhancesMdm2-dependent p53 ubiquitination and subsequently leadsto p53 polyubiquitination and degradation In other wordsthe nuclear FAKrsquos FERM domain enables mediating p53turnover in regulation of cell proliferation and survival [37]Accordingly mammary tumor malignancy and progressionoriginated from the loss of p53 expression or overexpressionof a dominant-negative p53R270H mutant are impeded uponFAK deletion [38] Thus FAK modulates cancer cell prolif-eration by either regulating cell cycle-relative molecules orpromoting tumor suppressor turnover

22 FAK Signaling in Cancer Cell Migration Invasionand Metastasis

221 FAK Signaling-Mediated Cytoskeleton Remodelling inCellMigration Cytoskeletal remodelling is critical for cancercell migration therefore indispensable for cancer metas-tasis FAK signaling which resulted from ECM-inducedintegrin clustering intimately involves in the reorganizationof cytoskeleton and cell motility In response to specificchemoattractant signals such as ECMs and growth factorsprotrusions are formed at the leading edge by polymeriza-tion of actin filaments towards the cell plasma membranefollowing the formation of focal adhesion complexes whereactivated integrins render the recruitment and activationof FAK [39 40] Through the FAKSrc complex formationand kinase activity cell migration is profoundly affectedby the subsequent phosphorylated p130Cas in promotingthe formation of CasCrk complex [41] myosin light-chainkinase- (MLCK-) mediated focal adhesion disassembly [42]c-Jun N-terminal kinase- (JNK-) mediated phosphoryla-tion of paxillin in facilitating cytoskeleton reorganization[43] interactions with PI3-kinase andor Grb7 in governingintracellular signaling related to cell motility [44 45] andso on Beside the essential role for the focal adhesions


assembly integrin-mediated FAK signaling governs focaladhesion turnover (adhesion dynamic) to ensure a dynamicand complex process of the membrane protrusion duringcell migration For example enhanced extracellular signal-regulated kinase 2 (ERK2) activitymediated by the formationof the FAKSrc complex at focal adhesion sites leads toprotease Calpain 2 activation which subsequently allowsCalpain 2 to cleave the molecules for example FAK andtalin at the focal adhesion sites in facilitating focal adhesionturnover in motile cells [46ndash48]

FAK also impacts on the remodelling of actin cytoskele-ton and stabilization of focal adhesions through its effecton small GTPases [17] Small GTPases (ie RhoA Rac1and Cdc42) function as critical roles in cytoskeleton reor-ganization [49] RhoA affects cell-cell or cell-ECMs inter-action by inducing the change of cytoskeleton Rac1 plays arole in membrane ruffling via driving actin polymerizationand Cdc42 involves in the formation of filopodia throughinitiating actin filament assembly [49ndash51] Given to bear-ing GAP activity for RhoA and Cdc42 [52] Graf a FAKinteracting protein empowers FAK signaling in regulation ofactin cytoskeleton reorganization Alternatively the forma-tion of the FAKN-WASP complex leads to the activation ofCdc42 followed by engagement of Arp23 and actin filamentformation [53 54] Moreover FAK binds to p190RhoGEFwhich leads to the activation of Rho and maturation offocal adhesions in association with tumor migration [54]These studies provide evidence for FAK and its signaling insubstantially controlling RhoGTPases and subsequently vitalfor cytoskeletal reorganization

222 FAK Promotes Cancer Invasion Cancer invasiontoward the surroundings at the primary site is a critical eventfor tumor malignancy Numerous numbers of evidence indi-cate that FAK predominately involves in the promotion oftumor invasion implicating that FAK is a potential targetfor anticancer therapeutics In a coopted manner of receptortyrosine kinase and integrins the formation of the FAKSrccomplex reinforces FAK signaling through p130Cas to recruitthe Crk-Dock180-ELMO complex in promoting the acti-vation of Rac1 which in turn activates JNK protein andresults inMMPs production for ECMproteolysis [17 55]Theconsequence of MMP-mediated ECM proteolysis is pivotalfor cancer invasion that can be facilitated by FAK-mediatedsignaling in response tomobile signals Nevertheless prior tocell invasion cancer cells per se need to proceed with a devel-opmental and morphological alternation called epithelial-mesenchymal transition (EMT) a process to transdifferenti-ate epithelial cells intomotilemesenchymal cells [56] Epithe-lial cadherin (E-cadherin) is the major molecule residedwithin epithelial adherent junctions During the occurrenceof EMT degradation of E-cadherin is accordant with thedisruption of adherent junctions which allows the release ofcell-cell restriction and therefore promotes cancer invasion[49] Reportedly the phosphorylation of FAK at Tyr407and Tyr861 by the FAKSrc complex drives the interruptionof E-cadherin-mediated epithelial adherent junctions [57ndash59] Consistently transforming growth factor-120573- (TGF-120573-)

induced EMT because of downregulation of E-cadherin ismediated by the activation of FAK in a Src dependentmanner[60] In the process of cancer invasion the activation of FAKin cancer cells could transmit numerous downstream signalpathways in regulating a variety of cellular events includingcytoskeletal remodelling and EMT to control cell fate

223 FAK Promotes Cancer Metastasis In agreement withits essential role in cell migration FAK is inferred to becrucially involved in cancer metastasis due to the fact thatoverexpression and activation of FAK are often clinicallyassociated with cancer metastasis [54 61 62] Actually theTyr397 phosphorylation and kinase activity of FAK aresubstantiated to be important for the invasive phenotypeas well as cancer metastasis [63] Intrinsically FAK kinaseactivity has been emphasized in the promotion of can-cer metastasis by regulating the expression of MMP9 andurokinase plasminogen activator [64] In addition increasedFAK expression can rescue the miR-7 negative effect ontumor migration and invasion [65] Accordingly suppres-sion of FAK expression and signaling by RNA interference(RNAi) or dominant-negative mutants of FAK (ie FAK-related nonkinase FRNK) generally enables inhibiting FAK-triggered cancer metastasis [66ndash69] The fact is that FRNKexpression reducing the FAK phosphorylation on Tyr397and decreasing the formation of focal adhesions is attributedto its inhibitory effect on cancer metastasis in vivo ratherthan the FRNK-induced dormancy or apoptosis of cancercells [70] Moreover FRNK expression also disrupts theformation of v-SrcFAK complex which in turn inhibitsp130Cas activity and reduces the v-Src-stimulated ERK andJNK kinase activation leading to impair v-Src-mediatedcell invasion and metastasis [71] On the other hand usingRNAi targeting FAK to reduce the expression of FAK hasbeen observed in reduction of cancer metastasis in cervicallymph node metastasis of tongue cancer [66] Additionallyalthough a synergistic effect of FAK and epidermal growthfactor receptor (EGFR) is highlighted for their cooperationin the promotion of non-small cell lung cancer metastasisknockdown of FAK and EGFR expression using short hairpinRNA (shRNA) significantly inhibits cancer metastasis [72]These observations emphasize the important role for FAKin regulating tumor malignancy by directing cancer invasionand metastasis

23 FAK in Cancer Stem Cells In spite of being controversialcancer stem cells remain an attractive subject for under-standing underlying tumorigenesis and malignancy as wellas cancer therapeutics As defined cancer stem cells bearthe ability to self-renewal differentiate into versatile cancercell types and promote tumor progression [73] Additionalproperty in maintaining a relatively quiescent and long lifespan renders cancer stem cells more resistant to currentchemotherapies [74] Recently deletion of FAK in mammaryepithelial cells (MaECs) has been reported to affect breastcancer development that is suppression of mammary tumorformation and progression in the mammary tumor mouseMMTV-PyMV model [75] In that study impairment of the


cancer stem cell maintenance in FAK ablated MaECs hasbeen taken into account for the decreased tumorigenicityand metastasis of mammary tumors [75] Indeed loss ofFAK leads to less activation of the PI3K-AKT signaling andtherefore impedes MaCSC self-renewal and tumorigenicity[76] although a compensatory activity by Pyk2 a nonreceptortyrosine kinase of the FAK family might appear [76] Besidesthe role of integrinFAK signaling in the regulation ofcancer stem cells is observed in squamous cell carcinomas[77] Yet these studies remain unidentifying the mechanisticnature of FAK and its signaling involved in regulation ofcancer stemprogenitor cell population In this regard thedifferential role of kinase-dependent and kinase-independentfunctions of FAK in mammary stem cells (MaSCs) andluminal progenitors had been explored The kinase activ-ity is required for the sphere-forming of MaECs and theproliferation of luminal progenitor in contrast the kinase-independent function of FAK necessitates in ductal invasionand basal MaSC activity [78] Consequently the inhibitor ofFAK kinase activity is not efficient in targeting MaSC-likehumanbreast cancer cells comparedwith luminal progenitor-like basal breast cancer cells [78] Furthermore a functionaldefect of FAKon its Pro-878881motif leads to impairing FAKscaffolding in mediating endophilin A2 phosphorylation bySrc thereby leading to profound decreases in epithelial-mesenchymal transition (EMT) and MaCSC activities [79]Collectively these findings provide an intrinsic role for FAKin the regulation of cancer stem cells which entails FAK as anovel target for anticancer therapeutics by intervention of thecancer stem cell activity

3 FAK in Tumor Microenvironment

During cancer progression and malignancy tumor cells con-tinuously encounter with their surroundings in a dynamicand complicated manner Nevertheless tumor microenvi-ronment commonly indicates the solid-state extracellularmatrices (ECMs) resided soluble factors nonneoplasticcells including cancer-associated fibroblasts endothelialcells bone marrow progenitor cells and tumor-associatedmacrophages and so on [18] The communication betweencancer cells and tumor microenvironment is mainly attrib-uted by secreted soluble factors (eg growth factors cytok-ines and chemokines) and extracellular matrices remodelingenzymes (eg matrix metalloproteinases MMPs and tissueinhibitor of metalloproteinases and TIMPs) governing cell-cell and cell-EMC interactions as well as cell signaling events[80]

Tumor microenvironment is an essential and vital nichein support for the developmental process of tumors Asmentioned above in light of tumor microenvironmentalcues activation of FAK is capable of driving the integrin-and growth factor receptor-mediated signaling inside of a cellto ignite tyrosine phosphorylation cascades and reorganizecytoskeleton of tumor cells On the other hand how the FAKof tumor-associated cells resided within the tumor microen-vironment activated and contributing to tumor progression isexploring in recent years Herein the emerging roles of FAK

in the varied cell types of tumor microenvironments will bediscussed below

31 IntegrinsFAK Signaling in Response to ECMs in TumorMicroenvironment Cumulative deposition and remodelingof ECMs fabricating a stiffer tumor microenvironmentusually result in resided tumor cells losing the regularcytoskeletal organization [81] As cell adhesion receptorsintegrins possess specific and varied binding affinities withvarious ECM molecule compositions to provide a tensionalhomeostasis in response to the tense states of tumormicroen-vironments Authentically the mechanotransduction causedby the ECM stiffness enables reflecting on integrin-mediatedFAK signaling influences tumor progression [82] Increasedlysyl oxidase (LOX) activity has been highlighted responsiblefor the consequence of ECM stiffness due to its abilityfor collagen cross-link which is in accordance with thepromotion of cancer malignancy as well as invasiveness andmetastasis in varied cancers including breast cancer cells[83] brain tumor [84] and colorectal cancer progression[85] In response to the increment of tumor matrix-stiffnessactivation of FAK is also correlated with the clustering of1205731 integrin encountering with the stiffen matrices and thenelicits PI3KAKT signaling [86] In addition ECM stiffnessinitiated by LOX activation is also capable of activatingMYC-induced upregulation of miR-18a in need of 1205731 integrinclusteringThus reduction of FAK activity by a FAK inhibitoris proved to modulate the expression of miR-18a followedby lowing PTEN expression and elevating PI3KAKT sig-naling in promoting tumor invasion and metastasis [87]Moreover the activation of FAK through ECM stiffness canmodulate the intracellular structure and promote cell cycleprogression rather than cell migration [88] in which theFAKp130CasRac signaling pathway is responsible for S-phase entry in the aid of increased cyclin D1 [88] ECMstiffness-mediated FAK activation and FAK-regulated tumorbiological functions in distinctmalignant cancers suggest thatthe ECM-mediated FAK signal transduction might functionas a general and crucial point in tumor developmentalprocesses

32 Endothelial Cell FAK Contributes to Tumor AngiogenesisIn addition to tumor cells FAK also plays an essentialrole in endothelial cells involved in tumor progressionTumor angiogenesis as a process for the formation of newblood vessels is an essential step for the development oftumor malignancy Indeed FAK signaling is important toregulate angiogenesis in embryonic development as well aspathological angiogenesis (eg tumor angiogenesis) [89ndash92] The expression and activation of FAK are frequentlycorrelated with endothelial cell survival proliferation andmigration [93 94] For example VEGF-AVEGF-receptor2 signaling induces the FAKPI3K complex formation bywhich endothelial cells migration is promoted to facilitateangiogenesis [95] In addition FAK phosphorylation medi-ated by angiopoietin-1 stimulation also enhances endothelialcell sprouting in a PI3K dependent manner [96] MoreoverFAK-deleted endothelial cells reduce tumor angiogenesis


which is caused by reduction of VEGF-mediated AKT phos-phorylation [89] In tumor-associated endothelial cells FAKactivity is essential for VEGF-mediated tumor extravasationand metastasis [97] Collectively FAK contributes to tumordevelopment in diverse mechanisms Realization of FAK-mediated signaling highlights and provides the opportunitiesin the development of anticancer therapeutics

33 FAK in Tumor-Associated Macrophages Tumour-asso-ciated macrophages (TAMs) play a protumoral role via stim-ulation of angiogenesis and enhancement of tumor cellinvasion migration andmetastasis TAMs are also immuno-suppressive preventing tumor cell attack by T cells andNK cells during tumor progression and after recoveryfrom chemotherapy or radiotherapy [98] FAK signalingis required for macrophage motility induced by integrinengagement [99] Importantly inhibition of FAK signalingreduces the infiltration of macrophages into tumor tissues[100ndash102] FAK in TAMs is thought to be bioactive how-ever how FAK in TAMs regulates TAMs-mediated tumormalignancy is largely unknown Nevertheless the followingsindicate a potential protumoral role of FAK in TAMs

TAMs promote tumor growth and distant metastasis bysecretion of various kinds of proteins in the paracrine man-ners that induce tumor epithelial-mesenchymal transitioninvasion migration and angiogenesis [98] It is worth to notethat the effect of FAK in TAMs on the expression of theseproteins Epithelial-mesenchymal transition is induced in theinvading tumor cells by TGF-120573 that is expressed byTAMs andis regulated by FAK in fibroblast cells [98 103] The processof tumor migration requires matrix remodeling facilitatedby matrix metalloproteinase 9 that is regulated by FAK infollicular thyroid carcinoma cells and fibroblasts [104ndash106]In addition neovascularization is important to tumor growthand metastasis TAMs stimulate neovascularization by theproduction of VEGF and IL-8 [98 107] The expression ofVEGF is regulated by FAK in epithelial cells [108 109] aswell as the expression of IL-8 in fibroblast-like synoviocytesand epithelial cells [110 111] In addition to establishmentof a favorable microenvironment TAMs also inhibit theantitumor immune responses through the suppression ofcytotoxic functions and the induction of apoptosis in T cellsand NK cells Therefore TAMs attenuate tumor surveillancein the tumor progression and antitumor immunity elicitedby tumor-derived antigens released from therapy-mediateddying tumor cells [112] TGF-120573 expressed by TAMs is reg-ulated by FAK in fibroblast cells and can inhibit T cellseffector functions through the induction of regulatory T cells[98 103] Taken together FAK is important to the inductionof TAMs through the recruitment ofmacrophages into tumortissues and potentially execute protumoral functions throughthe ability to regulate the downstream gene expression Thepotential role of FAK in TAMs is largely unknown and worthto be investigated

34 FAK in Cancer-Associated Fibroblast Cancer-associatedfibroblasts (CAFs) within tumor stroma promote cancerdevelopment by secreting chemokines or growth factors to

govern several oncogenic signals in cancer cells endothe-lial cells and inflammatory cells [113 114] FAK had beenreported to involve in the regulation of CAFs Tumor-derivedlysyl oxidase-like 2 (LOXL2) promotes the expression of120572-smooth muscle actin (120572-SMA) and activates fibroblaststhrough integrin-mediated FAK activation and AKT signal-ing [115] Moreover inhibition of FAK leads to impairingthe phosphorylation of AKT as well as the reduction of theexpression of 120572-SMA [115] FAK activation is also importantto prevent the anoikis by providing the antiapoptotic signal inboth fibroblasts and epithelial cells which implies that FAK-mediated aberrant survival signals in normal cells might playsome functions in affecting the cancer development [116]On the other hand FAKminusminus fibroblasts block cell migrationthe reexpression of FAK and the kinase activity of FAK inFAKminusminus fibroblasts are required for cell migration andinvasive phenotype defects [63] Indeed loss of FAK inthe epidermis had been reported to reduce the malignantprogression of skin cancers by enhancing the apoptosis[117] In addition the activation of FAK might alter theorganization of tumor microenvironment and facilitate thecancer development in pancreatic ductal adenocarcinoma(PDA) [100] In PDAmousemodel inhibition of FAK impairscancer cells proliferation and leads to the decreased CAFsrecruitment [100] Based on the study about the prognosticgene-expression signature of CAFs in non-small cell lungcancer the modulation of focal adhesion signaling mightbe regulated by integrin and FAK signal transductions [118]These studies suggest that FAK is vital in the cancer devel-opment by regulating the cellular and biological functions ofCAFs

4 FAK in the Development ofTargeted Therapeutics

Overexpression of FAK has been clinically observed in pri-mary human sarcomas [119] human prostate carcinomas[120] human ovary carcinomas [121] human colorectalcarcinomas [122] and breast cancers [123] implicating therole of FAK in cancer development Experimental evidencealso indicates that FAK-mediated signaling and functionsintrinsically involve in the development of tumormalignancysuggesting that FAK is a promising target for anticancer ther-apies Eventually several approaches have been developed tomodulate the expression or activation of FAK including smallchemical inhibitors PF-573228 and VS-4718 in capableof blocking the autophosphorylation of FAK on Tyr397According to the aforementioned roles for FAK in cancersome inhibitors have been launched in phase I clinical trialfor anticancer therapies Besides targeting specific protein-protein interaction which prevents the transduction of FAK-mediated signaling is an alternative strategy for anticancertherapy The following will further summarize and discussrecent development and progression of FAK-related anti-cancer therapies

41 FAK in Human Cancers Several mechanisms have beenreasoned for the overexpression of FAK protein in human


cancer in correlation with the fak gene amplification Usingin situ hybridization increased dosage of the fak gene onchromosome 8q243 is invariantly observed in the cell linesderived from human cancers of lung breast and colon [124]Moreover gains in copy number of fak gene in invasivesquamous cell carcinomas also revealed in correlation withelevation of FAK protein and tumorigenesis [124] In addi-tion both primary colorectal cancers and colorectal livermetastases express high levels of FAKmRNA copy number aswell as FAK protein expression level [122] However elevatedFAK expression is not always correlated with gains on fakgene amplification For example in human head and necksquamous cell carcinoma not all cases with an amplificationof the fak gene displayed FAK protein overexpression [125]implicating a sophisticated posttranscriptional regulationinvolved in FAK expression and functions

By analyzing the 51015840 promoter region of the fak gene NF-120581Bandp53 transcription factors can bindwithin the FAKpro-moter region [126] However NF-120581B and p53 transcriptionfactors exhibit opposite activities in the regulation of FAKtranscription NF-120581B induces FAK transcription whereasp53 suppresses FAK transcriptional activity [126] In humanbreast and colon cancers FAK expression is significantlyincreased in tumors containing p53 mutations in compari-son to tumors bearing wild-type p53 [127 128] Moreovermissense p53 mutations in its DNA-binding domain thatis V173M R249M and R282M also confer to promote theFAK promoter activity [127] Furthermore miR-151 derivedfrom the intron 22 of the fak gene which is often coexpressedwith its host gene fak may also be regulated by p53 tran-scription factor in human hepatocellular carcinoma [129]The synergistic effect of miR-151 and FAK can stimulateRac1 Cdc42 and Rho GTPases signaling which in turnleads to enhancing cancer motility and invasion [129] Thesestudies imply that FAK expression and its biological functionsmay be modulated by the transcriptional regulators and itscoamplification miR-151

The upregulation of FAK has been specifically associatedwith liver metastases of colon cancer which infers a rolefor FAK in tumor invasiveness in vivo [130] Several studiessuggest that a coordinate modulation of FAK-mediated sig-nals and functions is crucial for tumor malignancy [131ndash133]Moreover the overexpression of FAK and phosphorylation ofFAKonTyr397 is frequently associatedwith tumormetastasisas well as poor patient prognosis [134ndash136] indicating acritical role for FAK in tumor progression and malignancyThese studies suggest that FAK could be functioned as apotential prognostic marker and anticancer candidate

42 Targeting Kinase Activity of FAK In agreement with theimportance of FAKkinase activity in FAK-mediated signalingand development of tumor malignancy ATP-competitivekinase inhibitors are capable of binding the ATP-bindingpocket of FAK to efficiently block FAK catalytic activityTheirpotency signaling effect and functional efficacy on tumormalignancies will be discussed as follows

PF-573228This compound is a bisamino pyrimidine deriva-tive with the half maximal inhibitory concentration (IC

50)

for the FAK catalytic activity at 4 nM whereas for FAKautophosphorylation on Tyr397 at 30ndash100 nM ImportantlyPF-573228 blocks cell migration in concomitant reductionin the disassembly of focal adhesions In contrast thiscompound fails to inhibit cell growth or induce cell apoptosis[137]

TAE226 This compound is a bisanilino pyrimidine deriva-tive TAE226 inhibits the phosphorylation of FAK and theFAK-mediated signaling such as AKT ERK and S6 ribo-somal protein in glioma [138] Subsequently the inhibitionof FAK signaling by TAE226 induces the cell cycle arrestand increases cancer apoptosis TAE226 also impairs gliomatumor adhesion migration and invasion [138] Besidesglioblastomas TAE226 is capable of accomplishing thedetachment and apoptosis of breast cancers but no effects onMCF-10A normal breast epithelial cells [139] In animalmod-els TAE226prolongs the survival ratewith breast cancer bonemetastasis [140] TAE226 also suppresses the growth andangiogenesis of oral squamous cell carcinoma in a xenograftmouse model [141] To be noted in addition to FAK kinaseactivity this compound also blocks the activation of poly(ADP-ribose) polymerase and caspase-3 [139] CurrentlyTAE226 has been undergone its efficacy test in the preclinicalphase

PND-1186 (Also Termed VS-4718) This compound is a sub-stituted pyridine reversible inhibitor for FAK activity withan IC

50at 15 nM in vitro [142] Not only reduction in cell

migration but also PND-1186 triggers cancer apoptosis in a3D environment via blockage of the FAKp130Cas tyrosinephosphorylation cascade and induction of caspase-3 acti-vation [142] Consistently PND-1186 impacts on oncogenicKRAS- and BRAF-stimulated MDA-MB-231 breast cancergrowth and metastasis by blocking FAK and p130Cas phos-phorylation [143] In the preclinical phase PND-1186 displaysanticancer efficacy in orthotropic breast cancer mouse mod-els At present PND-1186 is under phase I clinical trial

PF-562271 (Also Termed VS-6062) This compound is abisamino pyrimidine derivative as a FAK activity inhibitorwith an IC

50at 15 nmolL [144] In therapies for pancreatic

ductal adenocarcinomamodel PF-562271 inhibitsmigrationof cancer cells cancer-associated fibroblasts (CAFs) andtumor-associatedmacrophages (TAMs) [100] indicating thatPF-562271may exert a novel mechanism in inhibiting cancermetastasis by altering the tumor microenvironment PF-562271 has been on the progress of the clinical trial targetingadvanced solid tumors [145]

43 Alternative Mechanism to Block FAK-Mediated CellularFunctions Protein-protein interactions are a fundamentalevent for signal transductions and involved in the develop-ment of tumormalignancy Eventually recruitment and inter-action with the intracellular domain of growth factor recep-tors (eg insulin-like growth factor receptor-1 IGF-1R andvascular endothelial growth factor 3 VEGFR-3) are requiredfor FAK activation essential for regulations of diverse sig-nal transductions in relation to cancer development These


observations prompt a possibility to interrupt the interactionbetween FAK and growth factor receptors for potentialanticancer therapeutics For example a small molecularcompound chloropyramine hydrochloride (calledC4) targetsthe interaction between FAK and VEGFR-3 which in turnreduces the phosphorylation of both proteins leading todecreasing the proliferation and causing the apoptosis inbreast cancer [146] Besides a compound INT2ndash31 targetsthe FAKIGF-1R complex and further effectively inhibitsAKT phosphorylation leading to decreasing melanoma cellsproliferation and tumor growth in vivo [147] Furthermorerather than disruptionwith growth factor receptors the 51015840-O-tritylthymidine (calledM13) compound blocks the formationof the FAKMdm-2 complex subsequently it activates p53and caspase-8 leading to increase detachment and apop-tosis in breast and colon cancers [148] Likewise a smallmolecule compound R2 can disrupt the interaction betweenFAK and p53 which in turn increases p53 transcriptionalactivity contributing to inhibit tumor growth [149] Thesecompounds target FAK scaffold which is a critical strategy toblock the FAK-mediated cancer development

Alternatively RNA interference (RNAi) is an emergingmeans for anticancer therapies Using RNAi to inhibit FAKexpression it can lead to the death of anoikis-resistant tumorcells and also reduce the metastasis of pancreatic cancerin a mouse model [27] Simultaneous inhibition of bothFAK and EGFR expression by specific shRNAs exhibits asynergistic effect on lung cancer metastasis in vivo [72]In addition ectopic expressions of miR-138 and miR-135targeting the FAK 31015840UTR reportedly suppress FAK-mediatedtumor growth and invasion as well as drug sensitivity [150]miR-7 also serving as a direct regulator of FAK expression bytargeting the FAK 31015840UTR as expected enables suppressingthe FAK-mediated malignancies in aggressive breast can-cers such as proliferation anchorage independent growthmigration and invasion [65] Besides the dominant-negativemutants of FAK (ie FAK-related nonkinase FRNK) mayalso provide an alternativeway to block FAK-triggered cancermalignancy [66ndash69] These strategies via targeting FAKmRNA or FAK-mediated protein-protein interactionsignaltransduction advance the development of FAK-targeted ther-apeutics

5 Conclusions

The kinase-dependent function and kinase-independentscaffolding ability of FAK are equivocally essential for cancerdevelopment Moreover the multifunctional characteristicsof FAK have been highlighted to modulate numerous signaltransductions in governing the activities and functions ofthe tumor microenvironment cancer cells andor cancerstem cells (Figure 1) However the complicated cross talkand regulatory loops modulated by FAK between the tumormicroenvironment and cancer cellscancer stem cells remainto be deciphered In lines of clinical observations overex-pression of FAK at both transcriptional and translationallevels in human varied cancers implies that FAK could be aprognostic marker and a potential anticancer candidate fortarget therapies In fact several small compounds targeting

the catalytic activity protein-protein interactions and evenRNAi of FAK have been launched for conducting clinicaltrials and some clarifications remain to be verified such asdrug sensitivity for specific types or stages of cancers appro-priate dosages side effects and the toxicity [151] Beyondthis the resistance of cancers to FAK inhibitor should bepondered deeply as the next problem Several studies indicatethat the combination of FAK inhibitor with chemotherapyor other anticancer molecules as a combinatory therapy forcancers effectively attenuates cancer development [146 152]Nevertheless the synergistic effect of the combination of FAKinhibitor and chemotherapy or other anticancer moleculesremains to be investigated for its possible regulatory mech-anisms in the anticancer therapy Collectively the profoundprogress during the past decades in themolecular and cellularmechanisms and cancer biology of FAK has provided muchbasic and clinical medical knowledge for targeting FAK as apotential anticancer therapeutic strategy

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Frontier Research Grant fromNational Taiwan University (103R78221 to T-L Shen) andMinistry of Science and Technology Taiwan (103-2320-B-002-046 to T-L Shen)

References

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[2] J L Guan J E Trevithick and R O Hynes ldquoFibronectinintegrin interaction induces tyrosine phosphorylation of a 120-kDa proteinrdquo Cell regulation vol 2 no 11 pp 951ndash964 1991

[3] M D Schaller C A Borgman B S Cobb R R Vines A BReynolds and J Thomas Parsons ldquopp125FAK a structurallydistinctive protein-tyrosine kinase associated with focal adhe-sionsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 89 no 11 pp 5192ndash5196 1992

[4] S K Hanks M B Calalb M C Harper and S K Patel ldquoFocaladhesion protein-tyrosine kinase phosphorylated in responseto cell attachment to fibronectinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 89 no18 pp 8487ndash8491 1992

[5] J Zhao and J-L Guan ldquoSignal transduction by focal adhesionkinase in cancerrdquoCancer andMetastasis Reviews vol 28 no 1-2pp 35ndash49 2009

[6] L A Cooper T L Shen and J L Guan ldquoRegulation of focaladhesion kinase by its amino-terminal domain through anautoinhibitory interactionrdquoMolecular and Cellular Biology vol23 no 22 pp 8030ndash8041 2003

[7] J M Dunty V Gabarra-Niecko M L King D F J CeccarelliM J Eck and M D Schaller ldquoFERM domain interactionpromotes FAK signalingrdquo Molecular and Cellular Biology vol24 no 12 pp 5353ndash5368 2004


[8] D Lietha X Cai D F J Ceccarelli Y Li M D Schaller andMJ Eck ldquoStructural basis for the autoinhibition of focal adhesionkinaserdquo Cell vol 129 no 6 pp 1177ndash1187 2007

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[10] D C Han T-L Shen and J-L Guan ldquoRole of Grb7 targetingto focal contacts and its phosphorylation by focal adhesionkinase in regulation of cell migrationrdquoThe Journal of BiologicalChemistry vol 275 no 37 pp 28911ndash28917 2000

[11] H R Reiske S-C Kao L A Cary J-L Guan J-F Lai andH-C Chen ldquoRequirement of phosphatidylinositol 3-kinase infocal adhesion kinase-promoted cell migrationrdquoThe Journal ofBiological Chemistry vol 274 no 18 pp 12361ndash12366 1999

[12] M D Schaller J D Hildebrand J D Shannon J W Fox RR Vines and J T Parsons ldquoAutophosphorylation of the focaladhesion kinase pp125FAK directs SH2-dependent binding ofpp60srcrdquoMolecular andCellular Biology vol 14 no 3 pp 1680ndash1688 1994

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[24] J C Horowitz D S Rogers V Sharma et al ldquoCombinatorialactivation of FAK and AKT by transforming growth factor-1205731 confers an anoikis-resistant phenotype to myofibroblastsrdquoCellular Signalling vol 19 no 4 pp 761ndash771 2007

[25] Y Zhang H Lu P Dazin and Y Kapila ldquoSquamous cell car-cinoma cell aggregates escape suspension-induced p53-mediated anoikis fibronectin and integrin 120572v mediate survivalsignals through focal adhesion kinaserdquoThe Journal of BiologicalChemistry vol 279 no 46 pp 48342ndash48349 2004

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[27] M S Duxbury H Ito M J Zinner S W Ashley and E EWhang ldquoFocal adhesion kinase gene silencing promotes anoikisand suppresses metastasis of human pancreatic adenocarci-noma cellsrdquo Surgery vol 135 no 5 pp 555ndash562 2004

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[32] J-H Zhao H Reiske and J-L Guan ldquoRegulation of the cellcycle by focal adhesion kinaserdquoThe Journal of Cell Biology vol143 no 7 pp 1997ndash2008 1998

[33] J Zhao R Pestell and J-L Guan ldquoTranscriptional activationof cyclin D1 promoter by FAK contributes to cell cycle progres-sionrdquoMolecular Biology of the Cell vol 12 no 12 pp 4066ndash40772001

[34] Q Ding J R Grammer M A Nelson J-L Guan J E StewartJr and C L Gladson ldquop27Kip1 and cyclin D1 are necessaryfor focal adhesion kinase regulation of cell cycle progression inglioblastoma cells propagated in vitro and in vivo in the scidmouse brainrdquo The Journal of Biological Chemistry vol 280 no8 pp 6802ndash6815 2005

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[38] M H A M van Miltenburg M J van Nimwegen I Tijdens etal ldquoMammary gland-specific ablation of focal adhesion kinasereduces the incidence of p53-mediated mammary tumour


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[42] D J Webb K Donais L A Whitmore et al ldquoFAK-Src sig-nalling through paxillin ERK and MLCK regulates adhesiondisassemblyrdquoNature Cell Biology vol 6 no 2 pp 154ndash161 2004

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[44] P-Y Chu L-Y Huang C-H Hsu et al ldquoTyrosine phosphory-lation of growth factor receptor-bound protein-7 by focal adhe-sion kinase in the regulation of cell migration proliferation andtumorigenesisrdquoThe Journal of Biological Chemistry vol 284 no30 pp 20215ndash20226 2009

[45] T L Shen D C Han and J L Guan ldquoAssociation of Grb7 withphosphoinositides and its role in the regulation of cell migra-tionrdquo The Journal of Biological Chemistry vol 277 no 32 pp29069ndash29077 2002

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crucial for ras transformation of fibroblastsrdquo The Journal ofBiological Chemistry vol 279 no 28 pp 29060ndash29065 2004

[56] S Lamouille J Xu and R Derynck ldquoMolecular mechanisms ofepithelial-mesenchymal transitionrdquo Nature Reviews MolecularCell Biology vol 15 no 3 pp 178ndash196 2014

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[64] S K Mitra S-T Lim A Chi and D D Schlaepfer ldquoIntrinsicfocal adhesion kinase activity controls orthotopic breast carci-noma metastasis via the regulation of urokinase plasminogenactivator expression in a syngeneic tumor modelrdquo Oncogenevol 25 no 32 pp 4429ndash4440 2006

[65] X Kong G Li Y Yuan et al ldquoMicroRNA-7 inhibits epithelial-to-mesenchymal transition andmetastasis of breast cancer cellsvia targeting FAK expressionrdquo PLoS ONE vol 7 no 8 ArticleID e41523 2012

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[72] C Li X Zhang L Cheng et al ldquoRNA interference targetinghuman FAK and EGFR suppresses human non-small-cell lungcancer xenograft growth in nude micerdquo Cancer Gene Therapyvol 20 no 2 pp 101ndash108 2013

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[74] M Dean T Fojo and S Bates ldquoTumour stem cells and drugresistancerdquo Nature Reviews Cancer vol 5 no 4 pp 275ndash2842005

[75] M Luo H Fan T Nagy et al ldquoMammary epithelial-specificablation of the focal adhesion kinase suppresses mammarytumorigenesis by affecting mammary cancer stemprogenitorcellsrdquo Cancer Research vol 69 no 2 pp 466ndash474 2009

[76] H Fan and J-L Guan ldquoCompensatory function of Pyk2protein in the promotion of focal adhesion kinase (FAK)-null mammary cancer stem cell tumorigenicity and metastaticactivityrdquo Journal of Biological Chemistry vol 286 no 21 pp18573ndash18582 2011

[77] M Schober and E Fuchs ldquoTumor-initiating stem cells ofsquamous cell carcinomas and their control by TGF-beta andintegrinfocal adhesion kinase (FAK) signalingrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 108 no 26 pp 10544ndash10549 2011

[78] M Luo X Zhao S Chen S Liu M S Wicha and J-L GuanldquoDistinct FAK activities determine progenitor and mammarystem cell characteristicsrdquo Cancer Research vol 73 no 17 pp5591ndash5602 2013

[79] H Fan X Zhao S Sun M Luo and J-L Guan ldquoFunctionof focal adhesion kinase scaffolding to mediate endophilin A2phosphorylation promotes epithelial-mesenchymal transitionand mammary cancer stem cell activities in vivordquo The Journalof Biological Chemistry vol 288 no 5 pp 3322ndash3333 2013

[80] F R Balkwill M Capasso and T Hagemann ldquoThe tumormicroenvironment at a glancerdquo Journal of Cell Science vol 125no 23 pp 5591ndash5596 2012

[81] D S Harburger and D A Calderwood ldquoIntegrin signalling at aglancerdquo Journal of Cell Science vol 122 no 2 pp 159ndash163 2009

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[83] S L Payne B Fogelgren A R Hess et al ldquoLysyl oxidaseregulates breast cancer cell migration and adhesion througha hydrogen peroxide-mediated mechanismrdquo Cancer Researchvol 65 no 24 pp 11429ndash11436 2005

[84] R Laczko KM SzauterMK Jansen et al ldquoActive lysyl oxidase(LOX) correlates with focal adhesion kinase (FAK)paxillinactivation and migration in invasive astrocytesrdquo Neuropathol-ogy and Applied Neurobiology vol 33 no 6 pp 631ndash643 2007

[85] A-M Baker D Bird G Lang T R Cox and J T Erler ldquoLysyloxidase enzymatic function increases stiffness to drive colorec-tal cancer progression through FAKrdquo Oncogene vol 32 no 14pp 1863ndash1868 2013

[86] K R Levental H Yu L Kass et al ldquoMatrix crosslinking forcestumor progression by enhancing integrin signalingrdquo Cell vol139 no 5 pp 891ndash906 2009

[87] J K Mouw Y Yui L Damiano et al ldquoTissue mechanics mod-ulate microRNA-dependent PTEN expression to regulate mali-gnant progressionrdquoNatureMedicine vol 20 no 4 pp 360ndash3672014

[88] Y H Bae K L Mui B Y Hsu et al ldquoA FAK-Cas-Rac-lam-ellipodin signaling module transduces extracellular matrixstiffness into mechanosensitive cell cyclingrdquo Science Signalingvol 7 no 330 p ra57 2014

[89] B Tavora S Batista L E Reynolds et al ldquoEndothelial FAK isrequired for tumour angiogenesisrdquo EMBOMolecular Medicinevol 2 no 12 pp 516ndash528 2010

[90] T-L ShenA Y-J ParkAAlcaraz et al ldquoConditional knockoutof focal adhesion kinase in endothelial cells reveals its role inangiogenesis and vascular development in late embryogenesisrdquoJournal of Cell Biology vol 169 no 6 pp 941ndash952 2005

[91] R Braren H Hu Y H Kim H E Beggs L F Reichardt andR Wang ldquoEndothelial FAK is essential for vascular networkstability cell survival and lamellipodial formationrdquoThe Journalof Cell Biology vol 172 no 1 pp 151ndash162 2006

[92] T R Polte A J Naftilan and S K Hanks ldquoFocal adhesionkinase is abundant in developing blood vessels and elevationof its phosphotyrosine content in vascular smooth musclecells is a rapid response to angiotensin IIrdquo Journal of CellularBiochemistry vol 55 no 1 pp 106ndash119 1994

[93] H Haskell M Natarajan T P Hecker et al ldquoFocal adhesionkinase is expressed in the angiogenic blood vessels of malignantastrocytic tumors in vivo and promotes capillary tube forma-tion of brain microvascular endothelial cellsrdquo Clinical CancerResearch vol 9 no 6 pp 2157ndash2165 2003

[94] L H Romer N McLean C E Turner and K Burridge ldquoTyro-sine kinase activity cytoskeletal organization and motility inhuman vascular endothelial cellsrdquoMolecular Biology of the Cellvol 5 no 3 pp 349ndash361 1994

[95] J H Qi and L Claesson-Welsh ldquoVEGF-induced activationof phosphoinositide 3-kinase is dependent on focal adhesionkinaserdquo Experimental Cell Research vol 263 no 1 pp 173ndash1822001

[96] I Kim H G Kim S-O Moon et al ldquoAngiopoietin-1 inducesendothelial cell sprouting through the activation of focal adhe-sion kinase andplasmin secretionrdquoCirculationResearch vol 86no 9 pp 952ndash959 2000

[97] C Jean X L Chen J-O Nam et al ldquoInhibition of endothelialFAK activity prevents tumor metastasis by enhancing barrierfunctionrdquo The Journal of Cell Biology vol 204 no 2 pp 247ndash263 2014

[98] RNoy and JW Pollard ldquoTumor-associatedmacrophages frommechanisms to therapyrdquo Immunity vol 41 no 1 pp 49ndash61 2014

[99] M Y Abshire K S Thomas K A Owen and A H BoutonldquoMacrophage motility requires distinct alpha5beta1FAK andalpha4beta1paxillin signaling eventsrdquo Journal of LeukocyteBiology vol 89 no 2 pp 251ndash257 2011

[100] J B Stokes S J Adair J K Slack-Davis et al ldquoInhibition offocal adhesion kinase by PF-562271 inhibits the growth andmetastasis of pancreatic cancer concomitant with altering thetumor microenvironmentrdquoMolecular Cancer Therapeutics vol10 no 11 pp 2135ndash2145 2011

[101] B Thapa B-H Koo Y-H Kim H-J Kwon and D-S KimldquoPlasminogen activator inhibitor-1 regulates infiltration ofmac-rophages into melanoma via phosphorylation of FAK-Tyr925rdquoBiochemical andBiophysical ResearchCommunications vol 450no 4 pp 1696ndash1701 2014

[102] P C Chen H C Cheng JWang et al ldquoProstate cancer-derivedCCN3 induces M2 macrophage infiltration and contributes toangiogenesis in prostate cancer microenvironmentrdquo Oncotar-get vol 5 no 6 pp 1595ndash1608 2014


[103] R Chen Z Zhang Z Xue et al ldquoFocal adhesion kinase (FAK)siRNA inhibits human hypertrophic scar by suppressing inte-grin 120572 TGF-120573 and 120572-SMArdquo Cell Biology International vol 38no 7 pp 803ndash808 2014

[104] T Chanmee P Ontong K Konno and N Itano ldquoTumor-associatedmacrophages asmajor players in the tumormicroen-vironmentrdquo Cancers vol 6 no 3 pp 1670ndash1690 2014

[105] B Rothhut C Ghoneim F Antonicelli and M Soula-RothhutldquoEpidermal growth factor stimulates matrix metalloproteinase-9 expression and invasion in human follicular thyroid carci-noma cells through Focal adhesion kinaserdquo Biochimie vol 89no 5 pp 613ndash624 2007

[106] Q Wang Y Wang D Fritz D Rajshankar G P Downey andC A McCulloch ldquoInteractions of the protein-tyrosine pho-sphatase-alpha with the focal adhesion targeting domain offocal adhesion kinase are involved in interleukin-1 signaling infibroblastsrdquoThe Journal of Biological Chemistry vol 289 no 26pp 18427ndash18441 2014

[107] S Ramanathan and N Jagannathan ldquoTumor associated mac-rophage a review on the phenotypes traits and functionsrdquoIranian Journal of Cancer Prevention vol 7 no 1 pp 1ndash8 2014

[108] J Zhu Y-S Wang J Zhang et al ldquoFocal adhesion kinase sig-naling pathway participates in the formation of choroidal neo-vascularization and regulates the proliferation and migrationof choroidal microvascular endothelial cells by acting throughHIF-1 and VEGF expression in RPE cellsrdquo Experimental EyeResearch vol 88 no 5 pp 910ndash918 2009

[109] E A Sheta M A Harding M R Conaway and D Theodor-escu ldquoFocal adhesion kinase Rap1 and transcriptional induc-tion of vascular endothelial growth factorrdquo Journal of theNational Cancer Institute vol 92 no 13 pp 1065ndash1073 2000

[110] L Neff M Zeisel V Druet et al ldquoERK 12- and JNKs-depend-ent synthesis of interleukins 6 and 8 by fibroblast-like synovio-cytes stimulated with protein III a modulin from oral strep-tococci requires focal adhesion kinaserdquo Journal of BiologicalChemistry vol 278 no 30 pp 27721ndash27728 2003

[111] J Eitel T Heise U Thiesen and P Dersch ldquoCell invasion andIL-8 production pathways initiated by YadA of Yersinia pseudo-tuberculosis require common signalling molecules (FAK c-SrcRas) and distinct cell factorsrdquo Cellular Microbiology vol 7 no1 pp 63ndash77 2005

[112] M R Shurin ldquoDual role of immunomodulation by anticancerchemotherapyrdquo Nature Medicine vol 19 no 1 pp 20ndash22 2013

[113] M M Mueller and N E Fusenig ldquoFriends or foesmdashbipolareffects of the tumour stroma in cancerrdquoNature Reviews Cancervol 4 no 11 pp 839ndash849 2004

[114] R Kalluri and M Zeisberg ldquoFibroblasts in cancerrdquo NatureReviews Cancer vol 6 no 5 pp 392ndash401 2006

[115] H E Barker D Bird G Lang and J T Erler ldquoTumor-secretedLOXL2 activates fibroblasts through fak signalingrdquo MolecularCancer Research vol 11 no 11 pp 1425ndash1436 2013

[116] N K Zouq J A Keeble J Lindsay et al ldquoFAK engages multiplepathways to maintain survival of fibroblasts and epitheliamdashdifferential roles for paxillin and p130Casrdquo Journal of CellScience vol 122 no 3 pp 357ndash367 2009

[117] G W McLean N H Komiyama B Serrels et al ldquoSpecificdeletion of focal adhesion kinase suppresses tumor formationand blocks malignant progressionrdquo Genes amp Development vol18 no 24 pp 2998ndash3003 2004

[118] R Navab D Strumpf B Bandarchi et al ldquoPrognostic gene-expression signature of carcinoma-associated fibroblasts in

non-small cell lung cancerrdquoProceedings of theNationalAcademyof Sciences of the United States of America vol 108 no 17 pp7160ndash7165 2011

[119] T M Weiner E T Liu R J Craven andW G Cance ldquoExpres-sion of focal adhesion kinase gene and invasive cancerrdquo TheLancet vol 342 no 8878 pp 1024ndash1025 1993

[120] L Tremblay W Hauck A G Aprikian L R Begin A Chapde-laine and S Chevalier ldquoFocal adhesion kinase (pp125119865119860119870)expression activation and association with paxillin and p50119862119878119870in human metastatic prostate carcinomardquo International Journalof Cancer vol 68 no 2 pp 164ndash171 1996

[121] P L Judson XHeWG Cance and L Van Le ldquoOverexpressionof focal adhesion kinase a protein tyrosine kinase in ovariancarcinomardquo Cancer vol 86 no 8 pp 1551ndash1556 1999

[122] A L Lark C A Livasy B Calvo et al ldquoOverexpression offocal adhesion kinase in primary colorectal carcinomas andcolorectal liver metastases immunohistochemistry and real-time PCR analysesrdquo Clinical Cancer Research vol 9 no 1 I pp215ndash222 2003

[123] L V Owens L Xu R J Craven et al ldquoOverexpression of thefocal adhesion kinase (p125FAK) in invasive human tumorsrdquoCancer Research vol 55 no 13 pp 2752ndash2755 1995

[124] M Agochiya V G Brunton D W Owens et al ldquoIncreaseddosage and amplification of the focal adhesion kinase gene inhuman cancer cellsrdquo Oncogene vol 18 no 41 pp 5646ndash56531999

[125] MCanel P Secades J P Rodrigo et al ldquoOverexpression of focaladhesion kinase in head and neck squamous cell carcinomais independent of fak gene copy numberrdquo Clinical CancerResearch vol 12 no 11 I pp 3272ndash3279 2006

[126] V Golubovskaya A Kaur and W Cance ldquoCloning and char-acterization of the promoter region of human focal adhesionkinase gene nuclear factor kappa B and p53 binding sitesrdquoBiochimica et Biophysica Acta Gene Structure and Expressionvol 1678 no 2-3 pp 111ndash125 2004

[127] VM Golubovskaya R Finch F Kweh et al ldquop53 regulates FAKexpression in human tumor cellsrdquo Molecular Carcinogenesisvol 47 no 5 pp 373ndash382 2008

[128] V M Golubovskaya K Conway-Dorsey S N Edmiston et alldquoFAKoverexpression and p53mutations are highly correlated inhuman breast cancerrdquo International Journal of Cancer vol 125no 7 pp 1735ndash1738 2009

[129] J Ding S Huang SWu et al ldquoGain ofmiR-151 on chromosome8q243 facilitates tumour cell migration and spreading throughdownregulating RhoGDIArdquo Nature Cell Biology vol 12 no 4pp 390ndash399 2010

[130] NMHan R Y Declan Fleming S A Curley andG E GallickldquoOverexpression of focal adhesion kinase (p125FAK) in humancolorectal carcinoma liver metastases independence from c-srcor c-yes activationrdquoAnnals of Surgical Oncology vol 4 no 3 pp264ndash268 1997

[131] M Abdel-Ghany H-C Cheng R C Elble and B U PaulildquoFocal adhesion kinase activated by beta(4) integrin ligationto mCLCA1 mediates early metastatic growthrdquo The Journal ofBiological Chemistry vol 277 no 37 pp 34391ndash34400 2002

[132] I Eke Y Deuse S Hehlgans et al ldquo1205731integrinFAKcortactin

signaling is essential for human head and neck cancer resistanceto radiotherapyrdquo The Journal of Clinical Investigation vol 122no 4 pp 1529ndash1540 2012

[133] T Shibue and R A Weinberg ldquoIntegrin 1205731-focal adhesionkinase signaling directs the proliferation of metastatic cancer


cells disseminated in the lungsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no25 pp 10290ndash10295 2009

[134] L V Owens L Xu G A Dent et al ldquoFocal adhesion kinase asa marker of invasive potential in differentiated human thyroidcancerrdquo Annals of Surgical Oncology vol 3 no 1 pp 100ndash1051996

[135] C Recher L Ysebaert O Beyne-Rauzy et al ldquoExpression offocal adhesion kinase in acute myeloid leukemia is associatedwith enhanced blast migration increased cellularity and poorprognosisrdquo Cancer Research vol 64 no 9 pp 3191ndash3197 2004

[136] A Albasri W Fadhil J H Scholefield L G Durrant and MIlyas ldquoNuclear expression of phosphorylated focal adhesionkinase is associated with poor prognosis in human colorectalcancerrdquoAnticancer Research vol 34 no 8 pp 3969ndash3974 2014

[137] J K Slack-Davis K H Martin R W Tilghman et al ldquoCellularcharacterization of a novel focal adhesion kinase inhibitorrdquoTheJournal of Biological Chemistry vol 282 no 20 pp 14845ndash14852 2007

[138] Q Shi A B Hjelmeland S T Keir et al ldquoA novel low-molecularweight inhibitor of focal adhesion kinase TAE226 inhibitsglioma growthrdquo Molecular Carcinogenesis vol 46 no 6 pp488ndash496 2007

[139] V M Golubovskaya C Virnig and W G Cance ldquoTAE226-induced apoptosis in breast cancer cells with overexpressed Srcor EGFRrdquoMolecular Carcinogenesis vol 47 no 3 pp 222ndash2342008

[140] N Kurio T Shimo T Fukazawa et al ldquoAnti-tumor effect inhuman breast cancer by TAE226 a dual inhibitor for FAK andIGF-IR in vitro and in vivordquo Experimental Cell Research vol 317no 8 pp 1134ndash1146 2011

[141] N Kurio T Shimo T Fukazawa et al ldquoAnti-tumor effect of anovel FAK inhibitor TAE226 against human oral squamous cellcarcinomardquo Oral Oncology vol 48 no 11 pp 1159ndash1170 2012

[142] I Tanjoni C Walsh S Uryu et al ldquoPND-1186 FAK inhibitorselectively promotes tumor cell apoptosis in three-dimensionalenvironmentsrdquo Cancer Biology and Therapy vol 9 no 10 pp764ndash777 2010

[143] C Walsh I Tanjoni S Uryu et al ldquoOral delivery of PND-1186FAK inhibitor decreases tumor growth and spontaneous breastto lung metastasis in pre-clinical modelsrdquo Cancer Biology ampTherapy vol 9 no 10 pp 778ndash790 2010

[144] W G Roberts E Ung P Whalen et al ldquoAntitumor activity andpharmacology of a selective focal adhesion kinase inhibitor PF-562271rdquo Cancer Research vol 68 no 6 pp 1935ndash1944 2008

[145] J R Infante D R Camidge L R Mileshkin et al ldquoSafety phar-macokinetic and pharmacodynamic phase I dose-escalationtrial of PF-00562271 an inhibitor of focal adhesion kinase inadvanced solid tumorsrdquo Journal of Clinical Oncology vol 30 no13 pp 1527ndash1533 2012

[146] E V Kurenova D L Hunt D He A TMagis D A Ostrov andW G Cance ldquoSmall molecule chloropyramine hydrochloride(C4) targets the binding site of focal adhesion kinase andvascular endothelial growth factor receptor 3 and suppressesbreast cancer growth in vivordquo Journal of Medicinal Chemistryvol 52 no 15 pp 4716ndash4724 2009

[147] D A Ucar E Kurenova T J Garrett et al ldquoDisruption ofthe protein interaction between FAK and IGF-1R inhibits mela-noma tumor growthrdquo Cell Cycle vol 11 no 17 pp 3250ndash32592012

[148] V M Golubovskaya N L Palma M Zheng et al ldquoAsmall-molecule inhibitor 51015840-o-tritylthymidine targets FAK and

Mdm-2 interaction and blocks breast and colon tumorigenesisin vivordquo Anti-Cancer Agents in Medicinal Chemistry vol 13 no4 pp 532ndash545 2013

[149] V M Golubovskaya B Ho M Zheng et al ldquoDisruption offocal adhesion kinase and p53 interaction with small moleculecompound R2 reactivated p53 and blocked tumor growthrdquoBMC Cancer vol 13 article no 342 2013

[150] V M Golubovskaya B Sumbler B Ho M Yemma and W GCance ldquoMiR-138 and MiR-135 directly target focal adhesionkinase inhibit cell invasion and increase sensitivity to chemo-therapy in cancer cellsrdquoAnti-Cancer Agents inMedicinal Chem-istry vol 14 no 1 pp 18ndash28 2014

[151] M E Roh M Cosgrove K Gorski and I S Hitchcock ldquoOff-targets effects underlie the inhibitory effect of FAK inhibitors onplatelet activation studies using Fak-deficient micerdquo Journal ofThrombosis and Haemostasis vol 11 no 9 pp 1776ndash1778 2013

[152] S N Hochwald C Nyberg M Zheng et al ldquoA novel smallmolecule inhibitor of FAK decreases growth of human pancre-atic cancerrdquo Cell Cycle vol 8 no 15 pp 2435ndash2443 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


the autophosphorylation of FAK on Tyr397 creates a high-affinity binding site for Src homology 2 (SH2) domain-con-taining proteins such as Src family kinases phosphoinositide3-kinase phospholipaseC and growth factor receptor-boundprotein 7 (Grb7) [9ndash12] thereby relying the upstream signalon versatile downstream signaling pathways Moreover thebinding of Src family kinases onto the phospho-Tyr397 ofFAK contributes to the promotion of FAK kinase activity andsignaling as a result of additional tyrosine phosphorylationson several tyrosine sites including Tyr407 Tyr576 Tyr577andTyr925 of FAK [5] In fact the phosphorylation of FAKonTyr576 and Tyr577 by Src leads to a steric effect on preventingan intramolecular interaction between the aminoterminalFERM domain and the kinase domain within FAK [13] Onthe other hand phospho-Tyr925 of FAK provides a dockingsite for growth factor receptor-bound protein 2 (Grb2)leading to activation of a RAS-MEKERK cascade [14 15]In addition the scaffolding functionality of FAK through itsphospho-tyrosine sites and two proline-rich motifs (mainlylocatedwithinC-terminus) has been observed and elaboratedin attribution with targeting a certain array of signalingproteins to focal adhesion sties in response to specific integrinactivation [16] Given the sophisticated regulated mechanismof FAK activation and signal transmission a myriad ofcellular and pathophysiological functions enable modulatedin a coopted manner stemming from integrin andor growthfactor activation Indeed via recruiting and phosphorylatingnumerous signaling proteins FAK empowers cell migrationand modulates cell proliferation adhesion apoptosis anddifferentiation in response to cell adhesion and mitogenstimulation [5 17] implicating in controlling a wide range ofprocesses of tumor [17] Inevitably the mechanistic nature ofFAK activation and signaling has been intensively studied tohighlight it as a potential target for anticancer therapeutics

Tumor microenvironment a mixture of varied cell typesas well as secreted cytokines and deposited ECMs is indis-pensable for tumor progression and metastasis [18 19]Upregulation of integrins and FAK is often observed to cor-relate with the progression of tumor development implyingthe integrinFAK signaling involved in regulation of tumordevelopment [20] Moreover the activation of FAK enablesmodulation by growth factor stimulation In this review weprovide an overview of FAK signaling in cancer cell biologyand discuss how FAK signal transduction controls the cancerdevelopment and progression as summarized in Figure 1 Inaddition we also summarize the potent anticancer drugs inrelation to FAK-mediated signaling

2 FAK in Cancer Cells

21 FAK Signaling in Cancer Cell Survival and Proliferation

211 FAK Regulates Cancer Survival FAK-mediated signal-ing plays a critical role in the regulation of cancer cell survivalIn opposite to cell adhesion anoikis is a form of programmedcell death due to the disruption of cell-ECM interactionsin which FAK activity is lost and therefore results in cellapoptosis [21 22] In contrast often overexpression of FAK

in cancer cells seems to attribute the resistance of celldetachment-induced cell death (ie anoiksis) Indeed inthese cancer cells the increased FAKSrc complex confers theactivation of both PI3K-AKT and MEK-extracellular signal-regulated kinase 12 (ERK12) signal transductions therebyenhancing the ability of cancer cell survival and growth ina cell detached condition [23] In addition several otherupstream signals also contribute to FAK-mediated anoikisresistance in cancer cells For example transforming growthfactor-120573 (TGF-120573) induces the activation of FAK and AKTvia SMAD3 and p38 MAPK respectively which in turnresults in anoikis resistance and tumor promotion [24]In squamous cell carcinoma (SCC) fibronectin-mediatedintegrin 120572V activation leading to FAK phosphorylation atTyr397 prevents suspension-induced or tumor suppressorp53-mediated anoikis [25] As expected disruption of theorganized fibronectin structure enables anoikis of SCCpresumably losing FAK phosphorylation and ERK activationMoreover overexpression of FAK has been shown to blockthe caspase-3-mediated apoptosis conversely inhibition ofFAK leads to apoptosis in cancer cells [26] Hence knock-down of FAK expression by RNA interference promotesanoikis and further inhibits pancreatic cancer metastasis invivo [27]

Antiapoptotic property is also essential for FAK in pre-vention of cancer programmed cell death Actually overex-pression of FAK apparently links to the activation of PI3K-AKT signal transduction and promotes the expression of NF-120581B-mediated inhibitor-of-apoptosis proteins (IAPs) whichwarrants apoptotic inhibition by blocking caspase-3 cascadein human leukemia [28] Likewise the phosphorylation ofNF-120581B and activation of PI3KAKT signaling modulated byFAK disable the tumor necrosis factor-120572- (TNF-120572-) inducedapoptosis [29] Moreover FAK also reportedly binds to thedeath domain kinase receptor-interacting protein (RIP) acomponent of death receptor complex in the programmedcell death by which FAK is capable of suppressing apoptosisby blocking the function of death domain of RIP [30] Thesestudies indicate that an essential role for FAK activation andFAK-mediated signal transduction is to direct the fate ofcancer cells by preventing the programmed cell death

212 FAK Regulates Cancer Proliferation Cell proliferationis a process of the increment of cell number as a result ofcell division and growth Discovery of the expression andtyrosine phosphorylation of FAK highly correlated with cellcycle progression by modulating cell cycle-relative molecules[31] highlights FAK functioning as a key regulator in pro-moting cancer proliferation Eventually overexpression ofFAK enables increasing cyclin D1 expression and decreasingcyclin-dependent kinase (CDK) inhibitor p21 expressionthereby accelerating G1 to S-phase transition Conversely thecompetition of FAK localization and function out from focalcontacts by a dominant-negative FAK mutant inhibits cellcycle progression at G1 phase [32] Furthermore FAK hasbeen elaborated to modulate the E26 transformation-specific(ETS) binding site resided within the cyclin D1 promoterwhich in turn regulates the transcriptional activation of


Cyclin D1

Cyclin EMdm2-p53

p21p27

Cas-Rac

IAPsMEK-ERK12

NF-120581BPI3K-AKT

RIPSMAD3



Cas-Crk



PI3KAngiopoietin-1

-SMA

Endophilin A2

TGF- and cytokines

PI3K

LOXL2

N-WASP-Cdc42-Arp23




Growth factor



FAK

Src

AKT

Cancer stem cell


Growth factor


FAK


FAKSrc



Endothelial cell

FAK AKT

FAK

AKT

ERKJNK

Antiapoptosis120572

120573




































50)













5 Conclusions





Acknowledgments


References











































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Cyclin D1

Cyclin EMdm2-p53

p21p27

Cas-Rac

IAPsMEK-ERK12

NF-120581BPI3K-AKT

RIPSMAD3



Cas-Crk



PI3KAngiopoietin-1

-SMA

Endophilin A2

TGF- and cytokines

PI3K

LOXL2

N-WASP-Cdc42-Arp23




Growth factor



FAK

Src

AKT

Cancer stem cell


Growth factor


FAK


FAKSrc



Endothelial cell

FAK AKT

FAK

AKT

ERKJNK

Antiapoptosis120572

120573




































50)













5 Conclusions





Acknowledgments


References











































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology































50)













5 Conclusions





Acknowledgments


References











































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
























50)













5 Conclusions





Acknowledgments


References











































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
















50)













5 Conclusions





Acknowledgments


References











































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology







50)













5 Conclusions





Acknowledgments


References











































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




5 Conclusions





Acknowledgments


References











































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






























Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Documents

Review Article Emerging Roles of Focal Adhesion Kinase in ...BioMed Research International Cyclin D 1 Cyclin E Mdm 2-p 53 p21 p27 Cas-Rac IAPs MEK-ERK 1/2 NF- B PI 3K-AKT RIP SMAD