Getting a grip on Thy-1 signaling

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<ul><li><p>5, U294-</p><p>la edgenicategvianalg. Aferens.</p><p>the bpite hyears.at, thorogene, brocells</p><p>s implunologof th</p><p>v 3</p><p>X 2</p><p>Biochimica et Biophysica Acta 1793 (2009) 921923</p><p>Contents lists available at ScienceDirect</p><p>Biochimica et Bi</p><p>e lssubtle and diverse phenotypic features. Its characterization has beensomewhat piecemeal, in keeping with the above observations. In theminds of many, Thy-1 has been relegated to the role of a meremarker; useful for identifying some broblasts, stem cells andneurons (in a colorful, even whimsical way in the case of the Thy-1-Brainbow transgenic mouse [2]), but failing to enter the pantheon ofvitally important molecules.</p><p>Part of Thy-1's scientic facelessness results from its lack of adened ligand; its failure to associate with molecules of interest. The</p><p>(p 150,95, CD11c/CD18) orM2 (Mac-1, CD11b/CD18) on leukocytes,promoting their adhesion and transendothelial migration [68].Melanoma cells appear to bind instead via v3 integrin to Thy-1 onactivated endothelium [9,10], which may facilitate melanoma metas-tasis. Thy-1 has been known to inhibit neurite outgrowth onastrocytes for many years [11]. Leyton et al initially described howthis interaction produces focal adhesion changes in astrocytes as well,and dened a role for 3 integrin in this heterotypic signaling [12].This group has continued to dissect this interaction, and the currentarticle by Hermosilla et al [1] addresses thclearly demonstrating, using a systematic, c</p><p> Corresponding author. Tel.: +1 205 9755224; fax: +E-mail addresses: thomas.barker@bme.gatech.edu (T</p><p>(J.S. Hagood).1 Tel.: +1 404 385 5039.</p><p>0167-4889/$ see front matter 2008 Elsevier B.V. Adoi:10.1016/j.bbamcr.2008.10.004it from the well-knownwhich no one has theouse is viable and has</p><p>the paradigm illustrated in the Hermosilla paper. Reported ligands forThy-1 trans- signaling are 2 and 3 integrins. Specically, humandermal microvascular endothelial cell (HDMEC) Thy-1 binds to blind men and the elephant metaphor, inbig picture. Furthermore, the Thy-1 null mhave tended to home in on one aspecparticular cell type. Thus the eld suft of the function of Thy-1, in afers a bThy-1 (CD90) is a developmenconserved cell surface glycoprotein,remains somewhat enigmatic despublications over the past forty-veThy-1 is still a bit mysterious is thubiquitous, it is expressed in a heteincluding thymocytes, lymphocyteshematopoietic and mesenchymal stemand some cancer cells. It therefore haelds, including neurobiology, immbiology and wound healing. In eachPart of the reason thatugh it is by no meansous range of cell types,blasts, neuronal cells,, ovarian follicular cells,ications in a number ofy, oncology, stem cellese areas, investigators</p><p>velopment and neural repair, and begin to paint a clearer picture ofThy-1's role with regard to signaling. The immunologic and non-immunologic functions of Thy-1 andwhat is known about its signalingmechanisms have been reviewed previously [35]; this mini-reviewwill focus on recent ndings in two broad paradigms in Thy-1signaling, attempt to put these ndings in a broader biological context,and suggest areas for future exploration.</p><p>Thy-1 can affect signaling heterotypically (in trans) by effectorcell Thy-1 binding to a Thy-1 ligand on a target cell (Fig. 1A). This isiological role of whichundreds of intriguing</p><p>inducing focal adhesion formation and cytoskeletal alterations viaRhoA GTPase activation. The ndings have implications for neurode-tally regulated, evolutionarily heterotypic binding of neuronal Thy-1 to integrin on astrocytes,Minireview</p><p>Getting a grip on Thy-1 signaling</p><p>Thomas H. Barker a,1, James S. Hagood b,a Biomedical Engineering, GA Tech/Emory, 313 Ferst Drive, Ste 3111 Atlanta, GA 30332-053b University of Alabama-Birmingham, 1670 University Blvd., 648A VH, Birmingham, AL 35</p><p>a b s t r a c ta r t i c l e i n f o</p><p>Article history:Received 19 March 2008Received in revised form 7 October 2008Accepted 8 October 2008Available online 25 October 2008</p><p>Keywords:Thy-1IntegrinNeuronAstrocyteContext-dependent signaling</p><p>A recent study by HermosilNham, P. Schneider, K. Burrineuron to astrocyte commuon neurons binds to v3 inadhesions and stress bersevidence regarding the sigcontext-dependent signalinsynthesize insights from difbehavior in both cis and tra</p><p>j ourna l homepage: www.is deciency in part byombinatorial approach,</p><p>1 205 9962333..H. Barker), jhagood@uab.edu</p><p>ll rights reserved.SA0019, USA</p><p>t al. [T. Hermosilla, D. Munoz, R. Herrera-Molina, A. Valdivia, N. Munoz, S.U., A.F. Quest, L. Leyton, Direct Thy-1/alphaVbeta3 integrin interaction mediatestion, Biochim Biophys Acta 1783 (2008) 11111120] demonstrates that Thy-1rin on astrocytes via a conserved RLD motif, triggering the formation of focaltyrosine phosphorylation and RhoA activation. This study adds to growinging mechanisms and biological roles of Thy-1, an important regulator ofs knowledge of Thy-1 approaches its ftieth year, it is critical to begin tont elds to determine how this heretofore enigmatic molecule modulates cell</p><p> 2008 Elsevier B.V. All rights reserved.</p><p>ophysica Acta</p><p>ev ie r.com/ locate /bbamcrstudy demonstrates denitively the role of the v3 heterodimer, andmore clearly denes the signaling in astrocytes downstream of v3[1]. A number of novel ndings are reported. The chain of the v3heterodimer identied by immunoprecipitation from DI TNC1 ratastrocytes was of smaller-than-expected molecular size, suggestingalternative splicing or post-translational modication. However, full-length v3 binds to Thy-1 in vitro by surface plasmon resonance.</p></li><li><p>ic sor thral</p><p>922 T.H. Barker, J.S. Hagood / Biochimica et Biophysica Acta 1793 (2009) 921923The v3 heterodimer is not normally expressed on adult astrocytes,but may be upregulated in response to injury. Hermosilla et al alsodemonstrate a requirement for the RLD tripeptide in Thy-1 in binding</p><p>Fig. 1. Thy-1 (CD90) Signaling. (A) Trans Signaling: Simplied scheme of Thy-1 heterotypnoted. (B) Cis Signaling: Colored dots in the light blue box correspond to colored text fregarding the signaling pathways involved, the reader is referred to the text and to seveto v3 integrin. This sequence is found within a highly conservedregion (70% humanratmouse homology in the 10 amino acidsanking RLD in both directions) of Thy-1, and is similar to the M2-binding region in brinogen [13]. It is suggested that other portions ofthe Thy-1 molecule, such as the GPI anchor, are not required for trans-signaling through v3, as Thy-1-Fc fusion protein on microspheresappears equally capable of mediating focal adhesion formation onastrocytes. This nding also would seem to negate the need for Thy-1in effector cells (e.g., neurons) to be present within lipid rafts. Thesignaling pathway stimulated by Thy-1 via v3 involves focaladhesion kinase (FAK) and RhoA GTPase. Interestingly, these arepathways which we have observed in association with homotypic (incis) Thy-1 signaling in pulmonary broblasts [1416], as discussedfurther below. The neuron-astrocyte interaction also involves Thy-1cis signaling in neurons (neurite outgrowth inhibition); however,the Thy-1-interacting molecules within neurons, and the downstreamsignaling pathways activated, have yet to be identied. Others haveshown that neurite outgrowth inhibition requires lipid raft integrity,as well as the Thy-1-specic GPI anchor [11].</p><p>Thy-1 also signals homotypically (in cis), through interactionwith TCR, via Thy-1 crosslinking, or through unknown mechanisms(Fig. 1B). The latter two must by necessity involve interaction withother molecules, as Thy-1 lacks a transmembrane or cytoplasmicportion. We and others have previously established Thy-1'sinteraction with members of the Src family kinases (SFKs; e.g.,via association of the GPI anchor with palmitoylated residues onSrc family members such as fyn and lyn [17]). Immunoprecipitationof Thy-1 from cell lysates co-precipitates SFKs [18]. Evidence for cissignaling of Thy-1 can be derived from pulmonary broblastsubpopulations sorted based on their surface expression of Thy-1.Thy-1-expressing broblasts display altered phenotypic responsesto growth factors, cytokines, and adhesion proteins. Theseresponses have been partially explained by regulation of down-stream signaling proteins such as phosphoinositide-3 kinase (PI3K)and SFKs. In response to the matricellular protein thrombospondin,</p><p>ignaling. Colored text indicates effector and responder cells for the downstream effectse cell types in which the indicated responses have been described. For further detailsrelevant reviews [35].Thy-1-expressing broblasts will disassemble focal adhesions in aPI3K- and SFK-mediated manner [15]. Lack of cell surface Thy-1abrogates this effect, which can be rescued by exogenous Thy-1expression following transfection. Furthermore, the baseline activityof the SFK-p190 Rho GTPase-activating protein (GAP) pathway isdependent on Thy-1 expression. Exogenous expression of Thy-1 onThy-1-nonexpressing broblasts results in inhibition of SFK activityand subsequent activation of RhoA, leading to focal adhesionassembly and stress ber formation [14]. Equally important to Thy-1 cis signaling is the integrity of lipid raft micro- and nanodomains.Through its GPI linkage, Thy-1 has been shown to have equalmobility in cholesterol-rich lipid rafts as in the bulk plasmamembrane, which facilitates its trafcking into and out of lipid raftdomains, whereas transmembrane proteins and other moieties aremore spatially restricted [19]. This inherent mobility may play arole in Thy-1's capacity to facilitate cis signaling as demonstratedby the fact that Thy-1 localization to lipid rafts and lipid raftintegrity appear critical to Thy-1's effect on signaling. Eitherreplacement of the GPI linkage with a membrane-spanning domainor disruption of lipid rafts with methyl-beta-cyclodextrin (MCD)disrupts Thy-1-mediated signaling [11,16]. Recently, strong evidencehas been presented that implies a role for Thy-1 in the associationof lipid rafts with the actin cortex immediately adjacent to theplasma membrane. Clustering of Thy-1 with antibody-coated goldnanoparticles followed by particle tracking demonstrates that Thy-1sorts into, resides within, and migrates out of distinct lipidnanodomains. The residence time within the nanodomains appearscontrolled by associations with the cell cytoskeleton [20]. Takentogether, these data are suggestive of a role of Thy-1 in thetrafcking and partitioning of signaling molecules into and out ofspecialized lipid rafts for higher order signaling networks asso-ciated with the cytoskeleton. In this way Thy-1 may act alternately</p></li><li><p>as an inhibitor, by sequestering, or facilitator, by trafcking, ofsignaling molecules such as SFKs.</p><p>In order to truly understand the effects of Thy-1 on signalingnetworks in both cis and trans, signicant further studies are required.</p><p>References</p><p>[1] T. Hermosilla, D. Munoz, R. Herrera-Molina, A. Valdivia, N. Munoz, S.U. Nham, P.Schneider, K. Burridge, A.F. Quest, L. Leyton, Direct Thy-1/alphaVbeta3 integrininteraction mediates neuron to astrocyte communication, Biochim. Biophys. Acta1783 (2008) 11111120.</p><p>923T.H. Barker, J.S. Hagood / Biochimica et Biophysica Acta 1793 (2009) 921923v3 via RLD is a signicant breakthrough, it is clear that Thy-1interacts with other cell surface molecules in a planar fashion. DoesThy-1 also associate with integrin in cis? The role of Thy-1 inregulating the Rho GTPases, focal adhesion assembly/disassembly,and stress ber formation are suggestive that cis interactions withintegrin occur, but studies are required to demonstrate this, as well asto systematically determine other Thy-1 binding partners. Further-more, the mechanisms regulating Thy-1 localization and trafcking tospecialized and distinct lipid nanodomains present a signicantchallenge that is likely to provide further insights into Thy-1's rolein coordinating signaling networks. Substitution of peptide sequencesthat direct GPI linkages in the endoplasmic reticulumwould allow theinterrogation of the effects of Thy-1 localization on signaling networksand downstream cell biology. The recent publications describing Thy-1's relative mobility and residence time in specic plasma membranedomains and the unexpected ability of Thy-1 to connect lipid rafts tounderlying cytoskeletal networks uncovers a completely unexploredtopic with direct relevance to Thy-1's documented activity inregulating cell cytoskeletal organization and changes.</p><p>The evidence for Thy-1 binding to integrin and regulation ofcytoskeletal signaling and organization make it ideally located toaffect critical cellular events, such as cell motility, mitotic lift-off,and potentially epithelial to mesenchymal transition. The fact thatthe molecule is shed from the surface [21,22] and could thusdirectly interact as a soluble factor, acting potentially as aninhibitor of cell adhesion, further complicates our understandingof the role of this protein in normal physiology and pathologicalprogression. What remains clear is that the expression of Thy-1 hassignicant consequences for the phenotype of many cells. Despiteour lack of understanding of the nuances of Thy-1 mechanisms, itis clear we can no longer be nave in the assumption that Thy-1 issimply a marker. It appears instead to be an integral protein indening cell behavior during normal homeostasis as well as duringtissue repair.</p><p>Other important aspects of Thy-1 biology not reviewed hereinclude evolution of Thy-1, regulation of Thy-1 expression, post-translational modication of Thy-1, including glycosylation andshedding, and potential interaction with lectins. Even by focusingmerely on Thy-1 signaling in cis and trans, however, it is clear thatThy-1 exerts signicant effects on signaling modulating cellcelland cellmatrix interaction, via interesting and possibly uniquemechanisms involving changes in both target and effector cells.Thy-1 thus emerges as an important modulator of context-dependent signaling, which alters interaction of cells with eachother and with their immediate environment. Some of the mostchallenging problems in biomedicine today are disorders ofneurodevelopment and neural repair after injury, regulation ofstem cell pluripotency and differentiation, cancer metastasis, andprogressive brotic diseases. Given the fact that Thy-1 has a role inall of these processes, the era of seeing Thy-1 as a marker, or ofcompartmentalized, nearsighted analysis of its function is over. AsThy-1 enters its second half-century, it is time to start looking atthe big picture.[2] J. Livet, T.A. Weissman, H. Kang, R.W. Draft, J. Lu, R.A. Bennis, J.R. Sanes, J.W.Lichtman, Transgenic strategies for combinatorial expression of uorescentproteins in the nervous system, Nature 450 (2007) 5662.</p><p>[3] S.M. Haeryfar, D.W. Hoskin, Thy-1: more than a mouse pan-T cell marker, J.Immunol. 173 (2004) 35813588.</p><p>[4] T.A. Rege, J.S. Hagood, Thy-1, a versatile modulator of signaling affecting cellularadhesion, proliferation, survival, and cytokine/growth factor responses...</p></li></ul>

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