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Review Articlep38120575MAPK Emerging Roles of a Neglected Isoform

Carol OrsquoCallaghan1 Liam J Fanning2 and Orla P Barry1

1 Department of Pharmacology andTherapeutics Western Gateway Building Western Road University College Cork Cork Ireland2Molecular Virology Diagnostic amp Research Laboratory Department of Medicine Clinical Sciences BuildingUniversity College Cork and Cork University Hospital Cork Ireland

Correspondence should be addressed to Orla P Barry obarryuccie

Received 23 June 2014 Revised 29 August 2014 Accepted 31 August 2014 Published 17 September 2014

Academic Editor Rony Seger

Copyright copy 2014 Carol OrsquoCallaghan et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

p38120575 mitogen activated protein kinase (MAPK) is a unique stress responsive protein kinase While the p38 MAPK family as awhole has been implicated in a wide variety of biological processes a specific role for p38120575 MAPK in cellular signalling and itscontribution to both physiological and pathological conditions are presently lacking Recent emerging evidence however providessome insights into specific p38120575MAPK signalling Importantly these studies have helped to highlight functional similarities as wellas differences between p38120575MAPK and the othermembers of the p38MAPK family of kinases In this reviewwe discuss the currentunderstanding of the molecular mechanisms underlying p38120575 MAPK activity We outline a role for p38120575 MAPK in importantcellular processes such as differentiation and apoptosis as well as pathological conditions such as neurodegenerative disordersdiabetes and inflammatory disease Interestingly disparate roles for p38120575MAPK in tumour development have also recently beenreported Thus we consider evidence which characterises p38120575 MAPK as both a tumour promoter and a tumour suppressor Insummary while our knowledge of p38120575MAPK has progressed somewhat since its identification in 1997 our understanding of thisparticular isoform in many cellular processes still strikingly lags behind that of its counterparts

1 p38 Isoform Evolution

The first and now archetypal member of the p38 MAPK fam-ily p38120572 MAPK was identified by four independent groupsin 1994 It was isolated as a 38 kDa protein rapidly tyrosinephosphorylated in response to lipopolysaccharide stimula-tion [1] as a molecule that binds pyridinyl-imidazole drugswhich inhibit the synthesis of proinflammatory cytokines[2] and as an activator of MAPK activated protein kinase 2(MAPKAP-K2MK2) and small heat shock proteins in cellsstimulated with heat shock or interleukin- (IL-) 1 [3 4]This was followed by the subsequent identification of p38120573MAPK in the same year p38120574 MAPK in 1996 and lastlyp38120575 MAPK in 1997 [5ndash9] The product of the S cerevisiaeHOG1 gene an important component of osmoregulationand the cell cycle was found to be a homologue of p38MAPK [10] This conservation from yeast to mammals issignificant as it indicates that the p38 family is responsiblefor critical cellular processes A study of the evolutionaryhistory of MAPKs suggests that each p38 MAPK family

member evolved from a single ancestor In fact it appearsthat MAPK12 (p38120574) arose from a tandem duplication ofMAPK11 (p38120573) on chromosome 22 while MAPK14 (p38120572)and MAPK13 (p38120575) subsequently resulted from a singlesegmental duplication of the MAPK11-MAPK12 gene unit onchromosome 6 [11] These gene duplications appear to haveoccurred before the species separation of nematodes but afterthe species separation of arthropods Interestingly unlikethe other p38 isoforms MAPK13 has not been identifiedin teleosts [11] This indicates that a MAPK13 gene deletionevent may have occurred subsequent to gene duplication inthe evolution of these species Duplicated genes are generallyassumed to be functionally redundant at the time of originand are eventually silenced The evolutionary preservation ofthe four p38 MAPK isoforms therefore suggests functionaldifferentiation of the individual family membersThus whilethe majority of research to date has focused on p38120572 andp38120573 MAPKs each isoform is an important kinase in itsown right with distinct cellular functions This review aimsto highlight components of the previously neglected p38120575

Hindawi Publishing CorporationInternational Journal of Cell BiologyVolume 2014 Article ID 272689 12 pageshttpdxdoiorg1011552014272689

2 International Journal of Cell Biology

MAPK signalling pathway and emphasises recent progressin our understanding of p38120575MAPK involvement in diversephysiological as well as pathological processes

The use of pyridinyl-imidazole inhibitors has largelydriven the advancement in our understanding of p38120572 andp38120573 MAPK signalling functions and substrates Bothp38120572 and p38120573 MAPK are highly sensitive to inhibition bySB203580 SB202190 andnewer compounds such as L-167307[2 5 12] In contrast the observation that p38120575 MAPK isinsensitive to inhibition by pyridinyl-imidazole compoundshas hindered its study in cellular events [7 9]The differentialsensitivity to these drugs can be attributed to amino acidsequence variability at the ATP binding pocket where thesecompounds bind competitively facilitated by interactionswith nearby amino acids Thr106 of p38120572 and p38120573 MAPKhas been identified as the major determinant for imidazoleinhibitor specificity as it orientates the drug to interact withHis107 and Leu108 thereby preventing ATP binding [13] Theequivalent residue in p38120575 MAPK is a methionine (Met)the large side chain of which prevents binding of theseinhibitors In fact substitution ofMet106 in p38120575MAPKwithThr was found to confer some sensitivity to inhibition bySB203580 [14] Conversely p38120572 MAPK mutants in whichThr106 is replaced with Met displayed reduced sensitivity toinhibition by SB203580 [15] It is unfortunate that no potentp38120575 MAPK specific inhibitor has been identified to dateAlthough the diaryl urea compound BIRB796 allostericallyinhibits p38120575 MAPK at high concentrations it is also apowerful inhibitor of p38120572 -120573 and -120574 MAPK [16] Whilevarying the concentration of BIRB796 and combining it withSB203580 may be of some use in identifying p38120575 MAPKspecific signalling pathways the possible influence of theother p38 MAPK isoforms in particular p38120574 MAPK mustbe considered when interpreting any results

2 p38120575MAPK Expression and Activation

Unsurprisingly p38120575 MAPK shares highly similar proteinsequences with the other p38 MAPK isoforms It displays61 59 and 65 amino acid identity to p38120572 -120573 and-120574MAPKs respectively [7] Differences in sequence betweenp38120575MAPKand the other p38MAPK familymembers can beobserved in the ATP binding pocket This has consequencesfor inhibitor sensitivity and contributes to substrate speci-ficity On the other hand the greatest sequence similaritieslie in the highly conserved kinase domains where the fourisoforms share gt90 amino acid identity [17] Within kinasesubdomain VIII (of XI) p38120575 MAPK possesses a TGYdual phosphorylation motif which is the hallmark of p38MAPKs and is conserved among all known mammalian p38isoforms [7ndash9 18] p38120575 MAPK has a distinct distributionprofile in human tissue that is relatively limited comparedto that of p38120572 and p38120573 MAPK isoforms which are largelyubiquitously expressed [8] High levels of p38120575 mRNA havebeen detected in endocrine tissues such as salivary pituitaryprostate and adrenal glands while more modest levels areexpressed in the stomach colon trachea pancreas skinkidney and lung [8] This differential expression in different

cell and tissue types is indicative of a specific biological effectof p38120575 MAPK activation in these cell types distinct fromthat of the other p38 family members

The murine p38120575 MAPK amino acid sequence is 92identical to the human sequence and the adultmouse displaysa broadly similar pattern of p38120575 MAPK expression to thatseen in human tissue that is lung testis kidney and gutepithelium [18] Murine p38120575 MAPK expression varies atdifferent stages in the developing mouse embryo At 95 daysit is primarily expressed in the developing gut and septumtransversum while by 155 days its expression expands tomost developing epithelia [18]This suggests that p38120575MAPKhas a role in embryonic development However knock-out ofp38120575MAPK results in mice which are both viable and fertileand exhibit a normal phenotype [19] Moreover while p38120573-and p38120574-null mice as well as p38120574p38120575 double knockout(KO) mice are also phenotypically normal [19 20] geneticablation of p38120572 MAPK is embryonic lethal at day 105ndash115[21] Functional redundancy among the p38 isoforms is alikely explanation with p38120572 -120573 or -120574 compensating for theloss of p38120575 MAPK activity during development Howeverit appears that p38120572 MAPK plays a critical role in earlydevelopment where its loss cannot be overcome

p38120572 -120573 and -120574 MAPK isoforms are activated byalterations in the physical and chemical properties of theextracellular environment with diverse triggers includingenvironmental stress signals inflammatory cytokines andmitogenic stimuli [1 5 6 22] Using transiently expressedepitope-tagged p38120575 MAPK a similar activation profile hasbeen defined for p38120575 MAPK [7ndash9] It is strongly activatedby environmental alterations in osmolarity ultraviolet (UV)irradiation and oxidation It is also moderately activated bychemical stressors and proinflammatory cytokines includingarsenite anisomycin tumour necrosis factor- (TNF-) 120572 andIL-1 Despite their similar activation profiles differences inthe levels of activation of p38120575 MAPK and the other p38MAPK isoforms have been reported For example whilehyperosmolarity appears to stimulate both p38120572 andp38120575 to asimilar degree under hypoosmotic conditions p38120572MAPKis more strongly activated than p38120575 MAPK [7] A range ofMAP3Ks have been implicated in the activation of the p38MAPK pathway including MLKs (mixed-lineage kinases)TAK1 (transforming growth factor120573 activated kinase 1) ASK1(apoptosis signal-regulating kinase 1) TAO (thousand-and-one amino acid) DLK1 (dual-leucine-zipper-bearing kinase1) MEKKs and ZAK1 (leucine zipper and sterile-120572 motifkinase 1) (Figure 1) To date their individual contribution top38120575 MAPK signalling in particular is not yet understood[23ndash28] Further upstream of the MAP3Ks is a complexnetwork involving members of the RasRho family of smallGTP-binding proteins and heterotrimeric G-protein coupledreceptors [29 30] This adds to the diversity of signallingfrom various stimuli contributing to the crosstalk betweenp38 MAPKs and other signalling pathways

The upstream direct activators responsible for dual phos-phorylation of the p38 MAPK TGY motif are the MAPKkinases (MKKs) p38120575MAPK is unique as it can be activatedby four separate MKKs the p38 MAPK specific MKK3and MKK6 and also the JNK MKKs-4 and -7 [7ndash9 18]

International Journal of Cell Biology 3

p38120575PP

MKK3MKK4MKK6

ASK1 TAK1 MLKs TAO MEKKs

GPCRs RhoGTPases STE20 kinases

UV irradiation oxidation cytokines anisomycin arsenite

Stathmin

P

eEF2KP

eEF2X

PRKD1P

DiabetesNeurodegenerative

diseaseMigration

Inflammation

Proliferationdifferentiationapoptosis

Transcription

Translation

P P

Cancer

H2O2

AP1ATF2CEBPc-mybElk1p53SAP-1SAP-2TonEBP

Tau

Figure 1 Schematic representation of the current understanding of p38120575MAPK signalling and activation A variety of extracellular stimulican activate theMAPK signalling pathway resulting in dual phosphorylation of p38120575MAPK Known substrates of active p38120575MAPK includetranscription factors structural proteins kinases and translation repressors Phosphorylated substrates affect several cellular processes andcontribute to the pathogenesis of diseases such as cancer diabetes and neurodegenerative and inflammatory conditions

However information regarding the specific contributionsof these individual MKKs to p38120575 MAPK activation indifferent cell types and under diverse conditions is lackingCurrent evidence suggests that activation of p38120575 MAPK issignificantly influenced by both the nature and the strength ofthe stimulus as well as the cell type involved This may be theresult of varying levels of expression of upstream componentsof the MAPK signalling cascade in different cell types Forexample MKK3 is the major direct activator of p38120575MAPKphosphorylation in response to UV radiation hyperosmoticshock and TNF120572 in mouse embryonic fibroblast (MEF) cells[31] It also appears to be the primary kinase responsible forp38120575 MAPK activation in response to transforming growthfactor-1205731 (TGF-1205731) as MKK3 deficiency impairs endogenousp38120575 activation by TGF-1205731 in murine glomerular mesangialcells [32] On the other hand MKK6 was identified as themajor activator of p38120575MAPK in KB (HeLa) cells subjectedto IL-1 anisomycin or osmotic stress [9] FurthermoreMKK7 is reported to be responsible for the activation of p38120575MAPK in 293T cells under peroxide stress mediated by thescaffolding action of islet brain-2 [33] Further complicatingthe current understanding of p38120575 MAPK activation is thelikelihood that in some cases the cooperation of two MKKsmay be necessary While MKK4 preferentially phosphory-lates JNK on Tyr MKK7 preferentially phosphorylates JNKonThr [34ndash36]Therefore it must be considered possible thatthe combined activity of these two MKKs may be requiredto fully phosphorylate p38120575 MAPK on both the Tyr andthe Thr residues Interestingly two reports outline a MKK-independent mechanism of activation for p38120572 MAPK via

autophosphorylation [37 38] While autophosphorylationactivity is detected in intrinsically active p38120575 mutants [3940] no such pathway has been observed which activates theendogenous p38120575MAPK isoform

An important factor in determining the biological con-sequences of p38120575 MAPK phosphorylation is the strengthand duration of the activation signal p38120575 MAPK activa-tion is largely transient with activation and downregulationoccurring within minutes of stimulation [17] This is due tothe regulatory action of protein phosphatases which againappears to be cell-type specific While MAPK phosphatase1 inactivates p38120575 MAPK in HEK293FT cells it does notinteract with p38120575 MAPK in the NIH3T3 cell line [4142] The protein serinethreonine phosphatases PP1 andPP2A have also been shown to be involved in p38120575 MAPKphosphorylation as okadaic acid (OA) a PP1PP2A inhibitorcauses increased p38120575 MAPK activity in human epidermalkeratinocytes [43]

3 Novel p38120575MAPK Substrates

While p38 MAPKs are proline-directed kinases substratespecificity is also determined by docking domains both inthe MAPK itself and in the target protein [44] Thereforealthough p38120575 MAPK substrate specificity overlaps to someextent with that of p38120572 -120573 and -120574MAPKs there are a num-ber of notable differences Common substrates of p38MAPKsinclude MBP PHAS-1 and transcription factors ATF2 SAP1Elk-1 and p53 (Figure 1) In contrast however substrates


Table 1 Known p38120575MAPK substrates and their biochemical functions

Substrate Function Consequences of phosphorylation

AP1 Transcription factor Activation of transcription involucrin expression keratinocytedifferentiation [58]

ATF2 Transcription factor Activation of transcription [7 9]CEBP Transcription factor Keratinocyte differentiation [59]c-myb Transcription factor c-myb degradation [109]eEF2K Inhibitory kinase eEF2 activation protein synthesis [53]Elk1 Transcription factor Activation of transcription [7 9]p53 Transcription factor p21 expression G1 phase arrest [9 110]PHAS-1 Translation repressor Dissociation from eIF4E activation of translation [7]PRKD1 Serine-threonine kinase Inhibition of PRKD1 activity [72]SAP-1 Transcription factor Activation of transcription [9]SAP-2 Transcription factor Activation of transcription [9]Stathmin Microtubule protein Cytoskeleton reorganisation [50]Tau Microtubule protein Microtubule assembly tau self-aggregation [46]TonEBPOREBP Transcription factor Impaired TonEBPOREBP transcriptional activity [41]AP1 activator protein 1 ATF2 activating transcription factor 2 CEBP CCAAT (cytosine-cytosine-adenosine-adenosine-thymidine)-enhancer-bindingprotein myb myeloblastosis eEF2K eukaryotic elongation factor 2 kinase eEF2 eukaryotic elongation factor 2 PHAS-1 phosphorylated heat- and acid-stableprotein 1 PRKD1 protein kinase D 1 SAP serum response factor accessory protein eIF4E eukaryotic translation initiation factor 4E

such as MAPK activated protein kinase 2 (MAPKAP-K2)and MAPKAP-K3 which are the major downstream kinasesof p38120572 and p38120573 MAPK are not phosphorylated by p38120575MAPK [7ndash9 45] (Table 1)

31 Tau At the time p38120575 MAPK was first described themicrotubule-associated protein tau was identified as a strongin vitro substrate for p38120575 MAPK [46] Tau is a componentof the cytoskeleton network and under normal conditionsit stabilises microtubule assembly by binding to 120573-tubulinPhosphorylation of tau at T50 by p38120575MAPK causes it to befunctionally modified and enhances its capacity to promotemicrotubule assemblyThis effect is seen in neuroblastoma inresponse to osmotic shock where tau T50 phosphorylationoccurs soon after p38120575MAPK activation aiding the adaptiveresponse of neurons to changes in osmolarity [46] It appearshowever that subsequent hyperphosphorylation of tau atadditional sites causes it to dissociate from the cytoskeletonthereby promoting its self-assembly [47] This aggregationdestabilises the microtubule network and contributes tothe development of neurofibrillary tangles [48] NotablyAlzheimerrsquos disease and other neurodegenerative disordersknown as tauopathies are characterised by the aggregationin the brain of these neurofilament structures [49] Thereis therefore a clearly defined role for p38120575 MAPK in thepathogenesis of neurodegenerative disease making it a goodpotential therapeutic target for these disorders

32 Stathmin There is further evidence of a role forp38120575 MAPK in cytoskeleton regulation as the microtubule-associated protein stathmin has also been characterised as agood p38120575 MAPK substrate in vitro and in transfected cellsexposed to osmotic shock [50] The normal physiological

role of stathmin is to sequester free tubulin and increasedepolymerisation of microtubules [51 52] It is possiblethat phosphorylation of stathmin by p38120575 MAPK blocks itsability to destabilise microtubules and as a result promotesmicrotubule polymerisation and enhances cell survival understress conditions

33 eEF2K In response to anisomycin stimulation p38120575MAPK has been shown to be the main p38 MAPK isoformwhich phosphorylates eukaryotic elongation factor 2 kinase(eEF2K) [53] Phosphorylation of eEF2K on Ser359 inacti-vates the kinase and as a result removes its inhibitory phos-phorylation of eEF2 eEF2 in turn promotes the movement ofthe ribosome along mRNA during translation [54] This sug-gests that by inhibiting eEF2K and consequently activatingeEF2 p38120575MAPK is responsible for driving the translation ofproteins associatedwith stress responses Consistent with thishypothesis is the observation that theMKK36-p38120575MAPK-eEF2K pathway in myeloid cells is implicated in the produc-tion of the proinflammatory cytokine TNF120572 in bacterial LPSinduced acute liver disease [55]These differences in substratespecificity in combination with its unique tissue distributionprofile demonstrate that despite similarities in stimuli theconsequences of p38120575MAPK can potentially be significantlydifferent to those of the other p38 MAPK isoforms

4 p38120575MAPK Function and New Roles inHuman Disease

Since the discovery of p38120575 MAPK in 1997 it has beenimplicated in a range of diverse physiological events namelydifferentiation apoptosis and cytokine production (Fig-ure 1) The greatest understanding of its involvement in these


cellular processes has been achieved from work using ker-atinocytes and the majority of these studies have previouslybeen reviewed [56 57] Research is now emerging whichestablishes p38120575 MAPK as a regulator of these processes inother cell types As a result in the past five years p38120575MAPKhas also been implicated in the pathogenesis of diabetesinflammatory diseases and cancer This progress has beenachieved with the development of p38120575 MAPK KO mousemodels which are proving to be a useful tool in elucidatingnovel roles for p38120575MAPK in vivo

41 Differentiation and Psoriasis A number of differentstudies have identified a role for p38120575 MAPK in ker-atinocyte differentiation a process critical for the precisecontrol of normal epidermal homeostasis p38120575 MAPKinduces keratinocyte differentiation by regulating the expres-sion of involucrin a marker of keratinocyte terminaldifferentiation [58ndash60] p38120575 MAPK activation by 12-O-tetradecanoylphorbol-13-acetate (TPA) calcium OA orgreen tea polyphenol corresponds with increased involucrinpromoter activity mRNA and protein expression as well asincreased levels and activity of AP1 and CEBP transcriptionfactors [58 59 61] Importantly these responses are observedin the presence of a p38120572120573MAPK inhibitor In addition p38120574MAPK is poorly expressed in keratinocytes [60] confirming aspecific role for p38120575MAPK Involucrin expression can alsobe further upregulated in keratinocytes coexpressing p38120575MAPK and PKC120578 -120575 or 120576 isoforms [59] Of note cholesterol-depleting agents and overexpression of MKK6MKK7 havepreviously been shown to induce involucrin expression viaactivation of p38120572 MAPK [60 62 63] This highlightsthe significance of the stimulus type in determining p38MAPK isoform activation A further role for p38120575 MAPKin keratinocyte differentiation was recently identified p38120575MAPK can regulate expression of ZO-1 an epidermal tightjunction membrane protein associated with keratinocytedifferentiation [64] Inhibition of p38120575 MAPK results indepletion of ZO-1 protein in calcium induced differentiatingkeratinocytes while other junction proteins remain unaf-fected [64] Psoriasis is a benign chronic inflammatory skincondition that is characterised by hyperproliferation and dif-ferentiation of keratinocytes as well as increased expressionof inflammatory cytokines Given the significant role p38120575MAPK plays in keratinocyte differentiation it is no surprisethat aberrant p38120575 MAPK signalling has been implicated inthe pathogenesis of psoriasis Expression of theMAPK13 geneis commonly upregulated in psoriasis [65] Furthermore anincrease in p38120575 (as well as -120572 and -120573) MAPK activity hasbeen detected in psoriatic lesions compared to nonlesionalpsoriatic skin After treatment for psoriasis phosphorylatedp38 MAPK levels return to those of uninvolved skin [66]

Further to its role in keratinocyte differentiation p38120575MAPK is also implicated in hematopoiesis In human pri-mary erythroid cells p38120575MAPKmRNA is only expressed inlate-stage differentiation where along with p38120572 MAPK it isincreasingly activated [67]Thismay suggest a functional rolefor p38120575 MAPK in erythrocyte membrane remodelling andenucleation Interestingly an increase in p38120575MAPKmRNA

and protein expression is observed as blood monocytesdifferentiate to macrophages [68] This suggests a role forp38120575MAPK in functions gained by mature macrophages Apossible candidate is phagocytosis given that the microtubuleassociated protein stathmin is such a strong p38120575 MAPKsubstrate

Most recently p38120575 MAPK has been identified as acomponent of differentiation in bone repair [69] In bonecell differentiation during wound healing wild type (WT)monocytes differentiate to calcifyingbone-formingmonoos-teophils upon treatment with the peptide LL-37 p38120575MAPKprotein and mRNA is highly expressed in monoosteophilscompared to undifferentiated monocytes Monocytes fromp38120575 MAPK KO mice are incapable of this differentiationsuggesting a critical role for p38120575MAPK in this process [69]

42 Apoptosis and Diabetes As well as its significant rolein keratinocyte differentiation p38120575 MAPK has also beenidentified as a regulator of keratinocyte apoptosis This dualfunctional role may be attributed to the overlap of differ-entiation and apoptosis signalling pathways [70] As wellas inducing involucrin expression [61] OA simultaneouslycauses disruption of mitochondrial membrane potential andcaspase-dependent apoptosis [43] Overexpression of p38120575MAPK enhances this OA driven apoptotic morphology Thisresponse is specific to p38120575MAPKactivation as it occurred inthe presence of the p38120572120573 MAPK inhibitor SB203580 [43]Furthermore p38120575 MAPK coexpressed with either MEK6or PKC120575 both upstream p38 MAPK activators elicited anapoptotic response similar to that induced by OA but in theabsence of an external stimulus This was also independentof SB203580 again ruling out a contribution from other p38MAPK isoforms [71] Interestingly concurrent p38120575 MAPKactivation and inactivation of the proproliferative MAPKERK12 were observed with OA stimulation and PKC120575p38120575MAPK coexpression [43 61 71] In fact a reduction in ERK12activation appears to be critical for apoptosis as its con-stitutive activation inhibited PKC120575p38120575 MAPK mediatedapoptosis [71] Therefore it is likely that a specific balancebetween prosurvival ERK12 and proapoptotic p38120575 MAPKis essential in determining keratinocyte fate In regulatingthis balance p38120575MAPK and ERK12 form a complex that istranslocated to the nucleus upon stimulation by PKC120575 Thisnuclear localisation facilitates ERK12 inactivation by nuclearphosphatases whilemaintaining p38120575MAPK activation [71]

A role for p38120575 MAPK in apoptosis has recently beendemonstrated in vivo using p38120575 MAPK KO mice Micedeficient in p38120575 MAPK displayed a fivefold lower rateof pancreatic 120573 cell death in response to oxidative stressthan WT mice and are afforded protection against insulinresistance induced by a high-fat diet [72] This would appearto link p38120575MAPK to the pathogenesis of diabetes mellitusa disease characterised by reduced insulin sensitivity anda decrease in insulin-producing pancreatic 120573 cells [72]Increased p38 MAPK pathway activity has indeed beenobserved in both type 1 and type 2 diabetes and is correlatedwith late complications of hyperglycemia including neuropa-thy and nephropathy [73 74] p38120575 MAPK specifically has


also been implicated in the regulation of insulin secretionPhosphorylation by p38120575 MAPK negatively regulates theactivity of protein kinaseD1 (PKD1) a knownpositive regula-tor of neuroendocrine cell secretion [72] Thus pronouncedactivation of PKD1 has been observed in pancreatic 120573 cellslacking p38120575MAPK As p38120575MAPK is normally quite highlyexpressed in the pancreas this can contribute to heightenedinsulin secretion and improved glucose tolerance in p38120575MAPK-null mice [72] The pivotal role p38120575 MAPK playsin integrating insulin secretion and survival of pancreatic 120573cells makes it an attractive potential therapeutic target for thetreatment of human diabetes

43 Cytokine Production and Inflammatory Diseases Oneof the pathways by which p38120572 MAPK was discoveredwas via its identification as a regulator of proinflammatorycytokine biosynthesis [2]Thus its role in cytokine signallingand cytokine-dependent inflammatory diseases is well char-acterised Consequently some recent research using p38120575MAPKKOmouse models has focused on identifying specificroles for p38120575 MAPK in inflammation A study of p38120575MAPK KO mice as well as myeloid-restricted deletion ofp38120575MAPK in mice has shown that p38120575MAPK is requiredfor the recruitment of neutrophils to sites of inflammation[75] p38120575MAPKand its downstream target PKD1 converselyregulate PTEN activity to control neutrophil extravasationand chemotaxis The accumulation of neutrophils at inflam-matory sites is known to trigger inflammation-induced acutelung injury (ALI) which can cause acute respiratory distresssyndrome (ARDS) a condition with a high mortality rate[76] Therefore abnormal p38120575-PKD1 signalling may play animportant role in both ALI and ARDS in humans

Rheumatoid arthritis is a typical example of an inflamma-tory disease involving chronic synthesis of proinflammatorycytokines which result in synovial hyperplasia and jointdestruction [77] While p38120575MAPK (along with -120572 -120573 and-120574) is expressed in the synovium of rheumatoid arthritispatients its level of activation is lower than that of the fourother p38 MAPK isoforms [78] Despite this low level ofactivation new research has identified p38120575 MAPK as anessential component of joint damage in a collagen-inducedmodel of arthritis p38120574120575minusminusmice displayed reduced arthritisseverity compared to WT mice [79] The decrease in jointdestructionwas associatedwith lower expression of IL-1120573 andTNF120572 as well as a reduction in T cell proliferation IFN120574 andIL-17 production Lack of either p38120574 or p38120575 MAPK aloneyielded intermediate effects suggesting significant roles forboth isoforms in arthritis pathogenesis

Proinflammatory cytokines also play a significant role inthe pathogenesis of inflammatory airway diseases includingasthma chronic obstructive pulmonary disease (COPD) andcystic fibrosisWhile increasedmucus production is linked tothe morbidity and mortality of such diseases the underlyingmolecular mechanisms remain somewhat unclear [80] Thecritical driver of mucus production is thought to be IL-13production by immune cells which results in mucin geneexpression [81 82] In the last few years p38120575 MAPK hasbeen implicated in the signalling pathway responsible forcontrolling IL-13 driven excess mucus production Increased

MAPK13 gene expression is evident in the lungs of patientswith severe COPD [83] Novel inhibitors with increasedactivity against p38120575 MAPK blocked mucus production byIL-13 in human airway epithelial cells [83] Thus in patientswith hypersensitivity airway diseases there exists a potentialopportunity for therapeutic intervention should specific p38120575MAPK inhibitors become clinically available

5 p38120575MAPK and Cancer

In recent years the function of the p38 MAPK signallingpathway in malignant transformation has been intensivelystudied As a result the best characterised isoform p38120572MAPK has been identified as both a tumour promoter [84ndash86] and a tumour suppressor [87ndash89] Recent studies havenow also implicated p38120575 MAPK in cancer developmentand progression Like p38120572MAPK p38120575MAPK would alsoappear to have both pro- and antioncogenic roles dependingon the cell type studied

Interest in p38120575 MAPK as a potential tumour promoteris based on the evidence that p38120575 MAPK expression andactivation are significantly increased in a variety of carcinomacell lines such as human primary cutaneous squamouscarcinoma cells [65] head and neck squamous carcinomacells and tumours [85] cholangiocarcinoma and liver cancercell lines [90] p38120575 MAPK was first shown to promote amalignant phenotype (over eight years ago) in head and necksquamous cell carcinoma (HNSCC) [85] It was shown toregulate HNSCC invasion and proliferation through control-ling expression of matrix metalloproteinase-1 and -13 [85 91]Moreover the expression of dominant-negative p38120575MAPKimpaired the ability of cutaneous HNSCC cells to implant inthe skin of immunodeficiency mice as well as inhibiting thegrowth of xenografts [85]

p38120575MAPK-null mice have been utilised to demonstratethat p38120575 MAPK is required for the development ofmultistage chemical skin carcinogenesis in vivo Whencompared with WT mice p38120575 MAPK-deficient micedisplayed reduced susceptibility to 7 12-dimethylbenz(a)anthracene12-O-tetradecanoylphorbol-13-acetate inducedskin carcinoma with a significant delay in tumourdevelopment [92] Furthermore both tumour numbersand size were significantly decreased compared with WTmice [92] This decreased carcinogenesis was associated withreduced levels of proproliferative ERK12-AP1 signalling anddecreased activation of signal transducer and activator oftranscription 3 (Stat3) [92] The ERK12-AP1 pathway is akey cancer promoting cascade previously implicated in skincarcinogenesis [93 94] Stat3 meanwhile is an oncogenictranscription factor involved in chemical and UVB-inducedtransformation [95] It is also proproliferative and playsa role in angiogenesis and invasion [96 97] Thereforep38120575 MAPK promotion of proliferation via Stat3 may be asignificant mechanism in the promotion of carcinogenesisby p38120575 MAPK Similarly p38120575 MAPK KO mice havereduced susceptibility to development of K-ras drivenlung tumorigenesis Compared with WT mice p38120575minusminusK-RasG12D+minus mice displayed significantly decreased tumournumbers average tumour volume and total tumour volume


per lung [92] This is in contrast to p38120572 MAPK-deficientmice which display hyperproliferation of lung epitheliumand increased K-Ras-induced lung tumour development[88] This highlights once again the distinct and oftenopposing functions of the individual p38 MAPK isoforms

Further evidence for a specific role of p38120575MAPK in pro-moting cancer progression has most recently been demon-strated in cholangiocarcinoma (CC) [90] p38120575 MAPKexpression is upregulated in CCwhen compared with normalbiliary tract tissue Knockdown however of p38120575 MAPKexpression by siRNA transfection significantly inhibitedmotility and invasiveness of CC cells In contrast overex-pression of p38120575 MAPK in these cells results in enhancedinvasive behaviour Significantly p38120575 MAPK may prove tobe a useful marker for the differential diagnosis of CC overhepatocellular carcinoma where it lacks expression [90]

In contrast to the relatively well characterised role ofp38120575MAPK as a tumour promoter an increasing number ofreports since 2011 outline its activity as a tumour suppressorThe first indication of a tumour suppressive role for p38120575MAPKwas observed in mouse embryonic fibroblasts (MEF)p38120575minusminus (and p38120574minusminus)MEFs displayed increased cellmotilitycompared to WT cells [98] Furthermore while WT fibrob-lasts ceased to proliferate after reaching 100 confluencyp38120575minusminus MEFs continued to grow forming foci rather thana monolayer [98] This deregulation of contact inhibition issignificant as it is a hallmark of malignant transformation[99] Our own recent studies have also identified a role forp38120575MAPK in the control of oesophageal squamous cell car-cinoma (OESCC)migration invasion and contact inhibitionprocesses which are crucial for the progression of primarytumours to distant metastases [100] Reintroduction of p38120575MAPK into OESCC cells which lack endogenous expressionsignificantly impaired cell proliferation migration and inva-sion as well as significantly reducing the number of coloniesformed on soft agar compared to WT These effects werefurther enhanced in cells transfected with a constitutivelyactive form of p38120575MAPK [100] Furthermore p38120575MAPKexpression appears to influence the chemosensitivity ofOESCC to apoptosis Our recent study indicates that OESCCcells expressing p38120575MAPK are significantly more sensitiveto cisplatin and 5-fluorouracil combination therapy thanp38120575 MAPK-deficient cells [101] These findings are signifi-cant as they suggest that p38120575MAPKmay be a useful predic-tor of response to chemotherapy in OESCC patients Furthersupporting the hypothesis that loss of p38120575 MAPK confersa survival advantage p38120575 MAPK expression was foundto be downregulated in brain metastases of triple-negativebreast cancer (TNBC) Abolition of p38120575 MAPK expressionin TNBC induced cell growth while overexpression of p38120575MAPK in brain metastases reduced growth rates [102]

Cancer genomes are increasingly associated with epige-netic alterations whereby tumour suppressor genes exhibitpromoter hypermethylation Interestingly hypermethylationof the MAPK13 gene promoter region has recently beencharacterised in both malignant pleural mesothelioma [103]and primary cutaneous melanoma [104] This methylation isassociated with downregulation of p38120575 MAPK mRNA and

protein expression Melanoma cell lines displaying MAPK13gene promotermethylation donot express significant levels ofp38120575MAPKwhen compared to fibroblasts melanocytes andmelanoma cell lines with unmethylated MAPK13 promotersFurthermore treatment ofmelanoma cells with the demethy-lating agent 5-aza-21015840-deoxycytidine significantly increasesthe expression of the MAPK13 gene [104 105] Importantlyreestablishment of p38120575MAPK expression inmelanoma cellswith MAPK13 hypermethylation suppresses cell prolifera-tion The effect was further enhanced upon expression ofa constitutively active form of p38120575 MAPK Interestinglyhowever overexpression of p38120575MAPK or its constitutivelyactive form in cells in which MAPK13 was not epigeneticallysilenced only marginally affected proliferation [104]

6 Conclusions and Future Directions for p38120575MAPK Research

p38120575 MAPK is a unique stress-responsive protein kinaseIt is mainly activated by environmental stresses includingUV radiation osmotic shock and oxidative stress to illicitan adaptive response within the cell This is mediatedthrough phosphorylation of substrates involved in cytoskele-ton organisation such as tau and stathmin as well as tran-scription factors responsible for the expression of stress-responsive genes [106 107] Since the discovery of the p38MAPK family in the mid-nineties they have increasinglybeen associated with cellular processes such as proliferationdifferentiation development apoptosis and migration [108]Research to date has generally focused on the first two iso-forms to be discovered It is now becoming increasingly clearhowever that conclusions drawn fromp38120572MAPK (and to anextent p38120573MAPK) studies cannot be automatically appliedto the p38120574 and p38120575 MAPK isoforms due to their differentexpression patterns substrate specificities and sensitivityto chemical inhibitors Studies carried out in the last fewyears have led to some small advances in our knowledge ofthe regulation of p38120575 MAPK and its physiological rolesIn particular the development of p38120575 MAPK KO mousemodels has yielded a greater understanding of the conse-quences of p38120575 MAPK signalling in vivo Roles for p38120575MAPK in important cellular processes such as differentiationand apoptosis have been identified [69 72] As a resultp38120575 MAPK is now implicated in a variety of pathologicalconditions including inflammatory diseases diabetes andcancer [72 75 92 98] Most importantly p38120575 MAPK maynow be considered as a potential therapeutic target for thetreatment of these disorders

The implication of p38120575MAPK in a wide range of humandiseases should strengthen future research interest in thisisoform The main limiting factors to the further study ofp38120575 MAPK functions however are the lack of specificinhibitors and activators Fuelled by the prospect of therapeu-tic benefit for patients with diabetes or inflammatory diseasefor example the search formore potent and specific inhibitorsof p38120575MAPK is ongoing [83] These may not only providepotential treatments for the conditions outlined here butcould also afford us the opportunity to delineate specific p38120575MAPK functions in the absence of involvement from other


p38MAPK isoformsThis in turnmay identify other diseaseswhere p38120575 MAPK could be a potential therapeutic targetIn this review we also present important and interestingobservations which suggest that focusing on identificationof specific p38120575 MAPK activators is also warranted Thismay in the future translate to the development of noveltherapeutic strategies for patients with OESCC ormelanomaWhether considering the possible therapeutic benefits ofp38120575 MAPK inhibitors or activators it is important to heedthe diversity and important role(s) of p38120575MAPK signallingin normal physiological processes In conclusion uncoveringsome of the physiological as well as pathological roles ofp38120575MAPK since its discovery almost twenty years ago hasbeen somewhat successful However based on our currentknowledge continued focused research on this particularisoform is necessary if p38120575 is to translate into a noveltherapeutic target for a range of diverse human diseases

Abbreviations

UV UltravioletGPCR G-protein coupled receptorGTP Guanine tyrosine phosphataseSTE20 Sterile 20ASK1 Apoptosis signal-regulating kinase 1TAK1 Transforming growth factor 120573 activated

kinase 1MLK Mixed-lineage kinaseTAO Thousand-and-one amino acidMEKK Mitogen activated protein kinase kinase

kinaseMKK Mitogen activated protein kinase kinasePRKD1 Protein kinase D 1AP1 Activator protein 1ATF2 Activating transcription factor 2CEBP CCAAT (cytosine-cytosine-adenosine-

adenosine-thymidine)-enhancer-binding protein

myb MyeloblastosisSAP Serum response factor accessory

proteineEF2K Eukaryotic elongation factor 2 kinaseeEF2 Eukaryotic elongation factor 2PHAS-1 Phosphorylated heat- and acid-stable

protein 1eIF4E Eukaryotic translation initiation factor

4E

Conflict of Interests

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

References

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[2] J C Lee J T Laydon P C McDonnell et al ldquoA protein kinaseinvolved in the regulation of inflammatory cytokine biosynthe-sisrdquo Nature vol 372 no 6508 pp 739ndash746 1994

[3] J Rouse P Cohen S Trigon et al ldquoA novel kinase cascadetriggered by stress and heat shock that stimulates MAPKAPkinase-2 and phosphorylation of the small heat shock proteinsrdquoCell vol 78 no 6 pp 1027ndash1037 1994

[4] N W Freshney L Rawlinson F Guesdon et al ldquoInterleukin-1 activates a novel protein kinase cascade that results in thephosphorylation of Hsp27rdquo Cell vol 78 no 6 pp 1039ndash10491994

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[6] Z Li Y Jiang R J Ulevitch and J Han ldquoThe primary structureof p38120574 a newmember of p38 group ofMAP kinasesrdquoBiochem-ical and Biophysical Research Communications vol 228 no 2pp 334ndash340 1996

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[10] J L Brewster T de Valoir N D Dwyer E Winter and M CGustin ldquoAn osmosensing signal transduction pathway in yeastrdquoScience vol 259 no 5102 pp 1760ndash1763 1993

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[41] X Zhou J D Ferraris N I Dmitrieva Y Liu and M B BurgldquoMKP-1 inhibits high NaCl-induced activation of p38 but doesnot inhibit the activation of TonEBPOREBP opposite roles ofp38120572 and p38120575rdquo Proceedings of the National Academy of Sciencesof the United States of America vol 105 no 14 pp 5620ndash56252008

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[103] Y Goto K Shinjo Y Kondo et al ldquoEpigenetic profiles distin-guish malignant pleural mesothelioma from lung adenocarci-nomardquo Cancer Research vol 69 no 23 pp 9073ndash9082 2009

[104] L Gao M A Smit J J van den Oord et al ldquoGenome-widepromoter methylation analysis identifies epigenetic silencing ofMAPK13 in primary cutaneous melanomardquo Pigment Cell andMelanoma Research vol 26 no 4 pp 542ndash554 2013

[105] Y Koga M Pelizzola E Cheng et al ldquoGenome-wide screen ofpromoter methylation identifies novel markers in melanomardquoGenome Research vol 19 no 8 pp 1462ndash1470 2009

[106] A Risco and A Cuenda ldquoNew insights into the p38gamma andp38delta MAPK pathwaysrdquo Journal of Signal Transduction vol2012 Article ID 520289 8 pages 2012

[107] A Cuadrado and A R Nebreda ldquoMechanisms and functions ofp38 MAPK signallingrdquo Biochemical Journal vol 429 no 3 pp403ndash417 2010

[108] J M Kyriakis and J Avruch ldquoMammalian MAPK signal trans-duction pathways activated by stress and inflammation a 10-year updaterdquo Physiological Reviews vol 92 no 2 pp 689ndash7372012


[109] E Pani and S Ferrari ldquop38MAPK120575 controls c-Myb degradationin response to stressrdquo Blood Cells Molecules and Diseases vol40 no 3 pp 388ndash394 2008

[110] W C Hawkes and Z Alkan ldquoDelayed cell cycle progressionin selenoprotein w-depleted cells is regulated by a mitogen-activated protein kinase kinase 4-p38c-Jun NH 2-terminalkinase-p53 pathwayrdquo Journal of Biological Chemistry vol 287no 33 pp 27371ndash27379 2012

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Zoology


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MAPK signalling pathway and emphasises recent progressin our understanding of p38120575MAPK involvement in diversephysiological as well as pathological processes

The use of pyridinyl-imidazole inhibitors has largelydriven the advancement in our understanding of p38120572 andp38120573 MAPK signalling functions and substrates Bothp38120572 and p38120573 MAPK are highly sensitive to inhibition bySB203580 SB202190 andnewer compounds such as L-167307[2 5 12] In contrast the observation that p38120575 MAPK isinsensitive to inhibition by pyridinyl-imidazole compoundshas hindered its study in cellular events [7 9]The differentialsensitivity to these drugs can be attributed to amino acidsequence variability at the ATP binding pocket where thesecompounds bind competitively facilitated by interactionswith nearby amino acids Thr106 of p38120572 and p38120573 MAPKhas been identified as the major determinant for imidazoleinhibitor specificity as it orientates the drug to interact withHis107 and Leu108 thereby preventing ATP binding [13] Theequivalent residue in p38120575 MAPK is a methionine (Met)the large side chain of which prevents binding of theseinhibitors In fact substitution ofMet106 in p38120575MAPKwithThr was found to confer some sensitivity to inhibition bySB203580 [14] Conversely p38120572 MAPK mutants in whichThr106 is replaced with Met displayed reduced sensitivity toinhibition by SB203580 [15] It is unfortunate that no potentp38120575 MAPK specific inhibitor has been identified to dateAlthough the diaryl urea compound BIRB796 allostericallyinhibits p38120575 MAPK at high concentrations it is also apowerful inhibitor of p38120572 -120573 and -120574 MAPK [16] Whilevarying the concentration of BIRB796 and combining it withSB203580 may be of some use in identifying p38120575 MAPKspecific signalling pathways the possible influence of theother p38 MAPK isoforms in particular p38120574 MAPK mustbe considered when interpreting any results

2 p38120575MAPK Expression and Activation

Unsurprisingly p38120575 MAPK shares highly similar proteinsequences with the other p38 MAPK isoforms It displays61 59 and 65 amino acid identity to p38120572 -120573 and-120574MAPKs respectively [7] Differences in sequence betweenp38120575MAPKand the other p38MAPK familymembers can beobserved in the ATP binding pocket This has consequencesfor inhibitor sensitivity and contributes to substrate speci-ficity On the other hand the greatest sequence similaritieslie in the highly conserved kinase domains where the fourisoforms share gt90 amino acid identity [17] Within kinasesubdomain VIII (of XI) p38120575 MAPK possesses a TGYdual phosphorylation motif which is the hallmark of p38MAPKs and is conserved among all known mammalian p38isoforms [7ndash9 18] p38120575 MAPK has a distinct distributionprofile in human tissue that is relatively limited comparedto that of p38120572 and p38120573 MAPK isoforms which are largelyubiquitously expressed [8] High levels of p38120575 mRNA havebeen detected in endocrine tissues such as salivary pituitaryprostate and adrenal glands while more modest levels areexpressed in the stomach colon trachea pancreas skinkidney and lung [8] This differential expression in different

cell and tissue types is indicative of a specific biological effectof p38120575 MAPK activation in these cell types distinct fromthat of the other p38 family members

The murine p38120575 MAPK amino acid sequence is 92identical to the human sequence and the adultmouse displaysa broadly similar pattern of p38120575 MAPK expression to thatseen in human tissue that is lung testis kidney and gutepithelium [18] Murine p38120575 MAPK expression varies atdifferent stages in the developing mouse embryo At 95 daysit is primarily expressed in the developing gut and septumtransversum while by 155 days its expression expands tomost developing epithelia [18]This suggests that p38120575MAPKhas a role in embryonic development However knock-out ofp38120575MAPK results in mice which are both viable and fertileand exhibit a normal phenotype [19] Moreover while p38120573-and p38120574-null mice as well as p38120574p38120575 double knockout(KO) mice are also phenotypically normal [19 20] geneticablation of p38120572 MAPK is embryonic lethal at day 105ndash115[21] Functional redundancy among the p38 isoforms is alikely explanation with p38120572 -120573 or -120574 compensating for theloss of p38120575 MAPK activity during development Howeverit appears that p38120572 MAPK plays a critical role in earlydevelopment where its loss cannot be overcome

p38120572 -120573 and -120574 MAPK isoforms are activated byalterations in the physical and chemical properties of theextracellular environment with diverse triggers includingenvironmental stress signals inflammatory cytokines andmitogenic stimuli [1 5 6 22] Using transiently expressedepitope-tagged p38120575 MAPK a similar activation profile hasbeen defined for p38120575 MAPK [7ndash9] It is strongly activatedby environmental alterations in osmolarity ultraviolet (UV)irradiation and oxidation It is also moderately activated bychemical stressors and proinflammatory cytokines includingarsenite anisomycin tumour necrosis factor- (TNF-) 120572 andIL-1 Despite their similar activation profiles differences inthe levels of activation of p38120575 MAPK and the other p38MAPK isoforms have been reported For example whilehyperosmolarity appears to stimulate both p38120572 andp38120575 to asimilar degree under hypoosmotic conditions p38120572MAPKis more strongly activated than p38120575 MAPK [7] A range ofMAP3Ks have been implicated in the activation of the p38MAPK pathway including MLKs (mixed-lineage kinases)TAK1 (transforming growth factor120573 activated kinase 1) ASK1(apoptosis signal-regulating kinase 1) TAO (thousand-and-one amino acid) DLK1 (dual-leucine-zipper-bearing kinase1) MEKKs and ZAK1 (leucine zipper and sterile-120572 motifkinase 1) (Figure 1) To date their individual contribution top38120575 MAPK signalling in particular is not yet understood[23ndash28] Further upstream of the MAP3Ks is a complexnetwork involving members of the RasRho family of smallGTP-binding proteins and heterotrimeric G-protein coupledreceptors [29 30] This adds to the diversity of signallingfrom various stimuli contributing to the crosstalk betweenp38 MAPKs and other signalling pathways

The upstream direct activators responsible for dual phos-phorylation of the p38 MAPK TGY motif are the MAPKkinases (MKKs) p38120575MAPK is unique as it can be activatedby four separate MKKs the p38 MAPK specific MKK3and MKK6 and also the JNK MKKs-4 and -7 [7ndash9 18]


p38120575PP

MKK3MKK4MKK6




Stathmin

P

eEF2KP

eEF2X

PRKD1P


diseaseMigration

Inflammation


Transcription

Translation

P P

Cancer

H2O2


Tau
















































Abbreviations








4E



References




























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


p38120575PP

MKK3MKK4MKK6




Stathmin

P

eEF2KP

eEF2X

PRKD1P


diseaseMigration

Inflammation


Transcription

Translation

P P

Cancer

H2O2


Tau
















































Abbreviations








4E



References




























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology










































Abbreviations








4E



References




























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






























Abbreviations








4E



References




























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






















Abbreviations








4E



References




























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology












Abbreviations








4E



References




























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



Abbreviations








4E



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

Documents

Review Article p38 MAPK: Emerging Roles of a Neglected Isoformdownloads.hindawi.com/journals/ijcb/2014/272689.pdf · 2019. 7. 31. · Review Article p38 MAPK: Emerging Roles of a