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Semin Thromb Hemost 2004; 30(4): 427-439
DOI: 10.1055/s-2004-833478
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Protein-Protein Interactions in Platelet αIIbβ3 Signaling

Charito S. Buensuceso1 , 2 , Elena G. Arias-Salgado2 , Sanford J. Shattil2
  • 1Assistant Professor, Division of Hematology-Oncology, Department of Medicine, University of California San Diego, La Jolla, California
  • 2Division of Vascular Biology, Department of Cell Biology, and the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California
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Publication History

Publication Date:
08 September 2004 (online)

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The major platelet integrin αIIbβ3 is the main receptor involved in platelet functions such as aggregation and spreading on extracellular matrix. Like all other integrins, αIIbβ3 is capable of transducing signals both from inside and outside of the cell. To mediate these functions, αIIbβ3 interacts with intracellular and transmembrane proteins. The identification of these proteins, as well as the study of their functions, has provided valuable insights into integrin-mediated function and signaling. This review summarizes the known proteins that directly interact with αIIbbβ3 and provides an overview of their roles in integrin function.

KEYWORDS

Integrin αIIbβ3 - platelets - signaling

REFERENCES

  • 1 Calderwood D A, Shattil S J, Ginsberg M H. Integrins and actin filaments: reciprocal regulation of cell adhesion and signaling.  J Biol Chem. 2000;  275 22607-22610
    CrossrefPubMedGoogle Scholar
  • 2 Liu S, Calderwood D A, Ginsberg M H. Integrin cytoplasmic domain-binding proteins.  J Cell Sci. 2000;  113 3563-3571
    PubMedGoogle Scholar
  • 3 Brakebusch C, Fassler R. The integrin-actin connection, an eternal love affair.  EMBO J. 2003;  22 2324-2333
    CrossrefPubMedGoogle Scholar
  • 4 Hemler M E. Integrin associated proteins.  Curr Opin Cell Biol. 1998;  10 578-585
    CrossrefPubMedGoogle Scholar
  • 5 Brown E J, Frazier W A. Integrin-associated protein (CD47) and its ligands.  Trends Cell Biol. 2001;  11 130-135
    CrossrefPubMedGoogle Scholar
  • 6 Hemler M E. Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain.  Annu Rev Cell Dev Biol. 2003;  19 397-422
    CrossrefPubMedGoogle Scholar
  • 7 Collier N C, Wang K. Purification and properties of human platelet P235. A high molecular weight protein substrate of endogenous calcium-activated protease(s).  J Biol Chem. 1982;  257 6937-6943
    PubMedGoogle Scholar
  • 8 Horwitz A, Duggan K, Buck C, Beckerle M C, Burridge K. Interaction of plasma membrane fibronectin receptor with talin-a transmembrane linkage.  Nature. 1986;  320 531-533
    CrossrefPubMedGoogle Scholar
  • 9 Jockusch B M, Bubeck P, Giehl K et al.. The molecular architecture of focal adhesions.  Annu Rev Cell Dev Biol. 1995;  11 379-416
    CrossrefPubMedGoogle Scholar
  • 10 Borowsky M L, Hynes R O. Layilin, a novel talin-binding transmembrane protein homologous with C-type lectins, is localized in membrane ruffles.  J Cell Biol. 1998;  143 429-442
    CrossrefPubMedGoogle Scholar
  • 11 Ling K, Doughman R L, Firestone A J, Bunce M W, Anderson R A. Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions.  Nature. 2002;  420 89-93
    CrossrefPubMedGoogle Scholar
  • 12 Pfaff M, Liu S, Erle D J, Ginsberg M H. Integrin beta cytoplasmic domains differentially bind to cytoskeletal proteins.  J Biol Chem. 1998;  273 6104-6109
    CrossrefPubMedGoogle Scholar
  • 13 Knezevic I, Leisner T M, Lam S C. Direct binding of the platelet integrin alphaIIbbeta3 (GPIIb-IIIa) to talin. Evidence that interaction is mediated through the cytoplasmic domains of both alphaIIb and beta3.  J Biol Chem. 1996;  271 16416-16421
    CrossrefPubMedGoogle Scholar
  • 14 Sampath R, Gallagher P J, Pavalko F M. Cytoskeletal interactions with the leukocyte integrin beta2 cytoplasmic tail. Activation-dependent regulation of associations with talin and alpha-actinin.  J Biol Chem. 1998;  273 33588-33594
    CrossrefPubMedGoogle Scholar
  • 15 Calderwood D A, Zent R, Grant R, Rees D J, Hynes R O, Ginsberg M H. The talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation.  J Biol Chem. 1999;  274 28071-28074
    CrossrefPubMedGoogle Scholar
  • 16 Patil S, Jedsadayanmata A, Wencel-Drake J D, Wang W, Knezevic I, Lam S C. Identification of a talin-binding site in the integrin beta(3) subunit distinct from the NPLY regulatory motif of post-ligand binding functions. The talin n-terminal head domain interacts with the membrane-proximal region of the beta(3) cytoplasmic tail.  J Biol Chem. 1999;  274 28575-28583
    CrossrefPubMedGoogle Scholar
  • 17 Rees D J, Ades S E, Singer S J, Hynes R O. Sequence and domain structure of talin.  Nature. 1990;  347 685-689
    CrossrefPubMedGoogle Scholar
  • 18 Yan B, Calderwood D A, Yaspan B, Ginsberg M H. Calpain cleavage promotes talin binding to the beta 3 integrin cytoplasmic domain.  J Biol Chem. 2001;  276 28164-28170
    CrossrefPubMedGoogle Scholar
  • 19 Xing B, Jedsadayanmata A, Lam S C. Localization of an integrin binding site to the C terminus of talin.  J Biol Chem. 2001;  276 44373-44378
    CrossrefPubMedGoogle Scholar
  • 20 Calderwood D A, Yan B, de Pereda J M et al.. The phosphotyrosine binding-like domain of talin activates integrins.  J Biol Chem. 2002;  277 21749-21758
    CrossrefPubMedGoogle Scholar
  • 21 Law D A, Nannizzi-Alaimo L, Phillips D R. Outside-in integrin signal transduction. Alpha IIb beta 3-(GP IIb IIIa) tyrosine phosphorylation induced by platelet aggregation.  J Biol Chem. 1996;  271 10811-10815
    CrossrefPubMedGoogle Scholar
  • 22 Garcia-Alvarez B, de Pereda J M, Calderwood D A et al.. Structural determinants of integrin recognition by talin.  Mol Cell. 2003;  11 49-58
    CrossrefPubMedGoogle Scholar
  • 23 Ulmer T S, Calderwood D A, Ginsberg M H, Campbell I D. Domain-specific interactions of talin with the membrane-proximal region of the integrin beta3 subunit.  Biochemistry. 2003;  42 8307-8312
    CrossrefPubMedGoogle Scholar
  • 24 Tadokoro S, Shattil S J, Eto K et al.. Talin binding to integrin beta tails: a final common step in integrin activation.  Science. 2003;  302 103-106
    CrossrefPubMedGoogle Scholar
  • 25 Vinogradova O, Velyvis A, Velyviene A et al.. A structural mechanism of integrin αIIbβ3 “inside-out” activation as regulated by its cytoplasmic face.  Cell. 2002;  110 587-597
    CrossrefPubMedGoogle Scholar
  • 26 Kim M, Carman C V, Springer T A. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins.  Science. 2003;  301 1720-1725
    CrossrefPubMedGoogle Scholar
  • 27 Calderwood D A, Fujioka Y, de Pereda J M et al.. Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling.  Proc Natl Acad Sci USA. 2003;  100 2272-2277
    CrossrefPubMedGoogle Scholar
  • 28 Monkley S J, Zhou X H, Kinston S J et al.. Disruption of the talin gene arrests mouse development at the gastrulation stage.  Dev Dyn. 2000;  219 560-574
    CrossrefPubMedGoogle Scholar
  • 29 Monkley S J, Pritchard C A, Critchley D R. Analysis of the mammalian talin2 gene TLN2.  Biochem Biophys Res Commun. 2001;  286 880-885
    CrossrefPubMedGoogle Scholar
  • 30 Bertagnolli M E, Locke S J, Hensler M E, Bray P F, Beckerle M C. Talin distribution and phosphorylation in thrombin-activated platelets.  J Cell Sci. 1993;  106 1189-1199
    PubMedGoogle Scholar
  • 31 Shattil S J, O’Toole T, Eigenthaler M et al.. Beta 3-endonexin, a novel polypeptide that interacts specifically with the cytoplasmic tail of the integrin beta 3 subunit.  J Cell Biol. 1995;  131 807-816
    CrossrefPubMedGoogle Scholar
  • 32 Li D, Desai-Yajnik V, Lo E, Schapira M, Abagyan R, Samuels H H. NRIF3 is a novel coactivator mediating functional specificity of nuclear hormone receptors.  Mol Cell Biol. 1999;  19 7191-7202
    PubMedGoogle Scholar
  • 33 Eigenthaler M, Hofferer L, Shattil S J, Ginsberg M H. A conserved sequence motif in the integrin beta3 cytoplasmic domain is required for its specific interaction with beta3-endonexin.  J Biol Chem. 1997;  272 7693-7698
    CrossrefPubMedGoogle Scholar
  • 34 Kashiwagi H, Schwartz M A, Eigenthaler M, Davis K A, Ginsberg M H, Shattil S J. Affinity modulation of platelet integrin alphaIIbbeta3 by beta3-endonexin, a selective binding partner of the beta3 integrin cytoplasmic tail.  J Cell Biol. 1997;  137 1433-1443
    CrossrefPubMedGoogle Scholar
  • 35 Gawaz M, Besta F, Ylanne J et al.. The NITY motif of the beta-chain cytoplasmic domain is involved in stimulated internalization of the beta3 integrin A isoform.  J Cell Sci. 2001;  114 1101-1113
    PubMedGoogle Scholar
  • 36 Ohtoshi A, Otoshi H. Analysis of beta3-endonexin mutants for their ability to interact with cyclin A.  Mol Genet Genomics. 2001;  266 664-671
    CrossrefPubMedGoogle Scholar
  • 37 Ohtoshi A, Maeda T, Higashi H, Ashizawa S, Yamada M, Hatakeyama M. beta3-endonexin as a novel inhibitor of cyclin A-associated kinase.  Biochem Biophys Res Commun. 2000;  267 947-952
    CrossrefPubMedGoogle Scholar
  • 38 Besta F, Massberg S, Brand K et al.. Role of beta(3)-endonexin in the regulation of NF-kappaB-dependent expression of urokinase-type plasminogen activator receptor.  J Cell Sci. 2002;  115 3879-3888
    CrossrefPubMedGoogle Scholar
  • 39 Golden A, Nemeth S P, Brugge J S. Blood platelets express high levels of the pp60c-src-specific tyrosine kinase activity.  Proc Natl Acad Sci USA. 1986;  83 852-856
    PubMedGoogle Scholar
  • 40 Huang M M, Bolen J B, Barnwell J W, Shattil S J, Brugge J S. Membrane glycoprotein IV (CD36) is physically associated with the Fyn, Lyn, and Yes protein-tyrosine kinases in human platelets.  Proc Natl Acad Sci USA. 1991;  88 7844-7848
    PubMedGoogle Scholar
  • 41 Stenberg P E, Pestina T I, Barrie R J, Jackson C W. The Src family kinases, Fgr, Fyn, Lck, and Lyn, colocalize with coated membranes in platelets.  Blood. 1997;  89 2384-2393
    PubMedGoogle Scholar
  • 42 Dorahy D J, Berndt M C, Burns G F. Capture by chemical crosslinkers provides evidence that integrin alpha IIb beta 3 forms a complex with protein tyrosine kinases in intact platelets.  Biochem J. 1995;  309 481-490
    PubMedGoogle Scholar
  • 43 Kralisz U, Cierniewski C S. Association of pp60c-src with alpha IIb beta 3 in resting platelets.  Biochem Mol Biol Int. 1998;  45 735-743
    PubMedGoogle Scholar
  • 44 Obergfell A, Eto K, Mocsai A et al.. Coordinate interactions of Csk, Src, and Syk kinases with [alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton.  J Cell Biol. 2002;  157 265-275
    CrossrefPubMedGoogle Scholar
  • 45 Horvath A R, Muszbek L, Kellie S. Translocation of pp60c-src to the cytoskeleton during platelet aggregation.  EMBO J. 1992;  11 855-861
    PubMedGoogle Scholar
  • 46 Clark E A, Brugge J S. Redistribution of activated pp60c-src to integrin-dependent cytoskeletal complexes in thrombin-stimulated platelets.  Mol Cell Biol. 1993;  13 1863-1871
    PubMedGoogle Scholar
  • 47 Klinghoffer R A, Sachsenmaier C, Cooper J A, Soriano P. Src family kinases are required for integrin but not PDGFR signal transduction.  EMBO J. 1999;  18 2459-2471
    Google Scholar
  • 48 Harrison S C. Variation on a Src-like theme.  Cell. 2003;  112 737-740
    CrossrefPubMedGoogle Scholar
  • 49 Arias-Salgado E G, Lizano S, Sarkar S, Brugge J S, Ginsberg M H, Shattil S J. Src kinase activation by direct interaction with the integrin {beta} cytoplasmic domain.  Proc Natl Acad Sci USA. 2003;  100 13298-13302
    CrossrefPubMedGoogle Scholar
  • 50 Yamaguchi H, Hendrickson W A. Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation.  Nature. 1996;  384 484-489
    CrossrefPubMedGoogle Scholar
  • 51 Sicheri F, Moarefi I, Kuriyan J. Crystal structure of the Src family tyrosine kinase Hck.  Nature. 1997;  385 602-609
    CrossrefPubMedGoogle Scholar
  • 52 Obergfell A, Buensuceso C, Shattil S J. Alpha IIb beta 3 functions as a molecular anchor for proteins that mediate integrin signaling.  Blood. 2002;  101 122a
    PubMedGoogle Scholar
  • 53 Buensuceso C, De Virgilio M, Shattil S J. Detection of integrin αIIbβ3 clustering in living cells.  J Biol Chem. 2003;  278 15217-15224
    CrossrefPubMedGoogle Scholar
  • 54 Su J, Muranjan M, Sap J. Receptor protein tyrosine phosphatase α activates Src-family kinases and controls integrin-mediated responses in fibroblasts.  Curr Biol. 1999;  9 505-511
    CrossrefPubMedGoogle Scholar
  • 55 Chan A C, Iwashima M, Turck C W, Weiss A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain.  Cell. 1992;  71 649-662
    CrossrefPubMedGoogle Scholar
  • 56 Muller B, Cooper L, Terhorst C. Molecular cloning of the human homologue to the pig protein-tyrosine kinase syk.  Immunogenetics. 1994;  39 359-362
    PubMedGoogle Scholar
  • 57 Coopman P J, Do M T, Barth M et al.. The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells.  Nature. 2000;  406 742-747
    CrossrefPubMedGoogle Scholar
  • 58 Inatome R, Yanagi S, Takano T, Yamamura H. A critical role for Syk in endothelial cell proliferation and migration.  Biochem Biophys Res Commun. 2001;  286 195-199
    CrossrefPubMedGoogle Scholar
  • 59 Tsujimura T, Yanagi S, Inatome R et al.. Syk protein-tyrosine kinase is involved in neuron-like differentiation of embryonal carcinoma P19 cells.  FEBS Lett. 2001;  489 129-133
    CrossrefPubMedGoogle Scholar
  • 60 Yamada T, Fujieda S, Yanagi S et al.. IL-1 induced chemokine production through the association of Syk with TNF receptor-associated factor-6 in nasal fibroblast lines.  J Immunol. 2001;  167 283-288
    PubMedGoogle Scholar
  • 61 Woodside D G, Obergfell A, Leng L et al.. Activation of Syk protein tyrosine kinase through interaction with integrin beta cytoplasmic domains.  Curr Biol. 2001;  11 1799-1804
    CrossrefPubMedGoogle Scholar
  • 62 Hato T, Pampori N, Shattil S J. Complementary roles for receptor clustering and conformational change in the adhesive and signaling functions of integrin alphaIIb beta3.  J Cell Biol. 1998;  141 1685-1695
    CrossrefPubMedGoogle Scholar
  • 63 Clark E A, Shattil S J, Ginsberg M H, Bolen J, Brugge J S. Regulation of the protein tyrosine kinase pp72syk by platelet agonists and the integrin alpha IIb beta 3.  J Biol Chem. 1994;  269 28859-28864
    PubMedGoogle Scholar
  • 64 Woodside D G, Obergfell A, Talapatra A, Calderwood D A, Shattil S J, Ginsberg M H. The N-terminal SH2 domains of Syk and ZAP-70 mediate phosphotyrosine-independent binding to integrin beta cytoplasmic domains.  J Biol Chem. 2002;  277 39401-39408
    CrossrefPubMedGoogle Scholar
  • 65 Lin T H, Rosales C, Mondal K, Bolen J B, Haskill S, Juliano R L. Integrin-mediated tyrosine phosphorylation and cytokine message induction in monocytic cells. A possible signaling role for the Syk tyrosine kinase.  J Biol Chem. 1995;  270 16189-16197
    CrossrefPubMedGoogle Scholar
  • 66 Yan S R, Huang M, Berton G. Signaling by adhesion in human neutrophils: activation of the p72syk tyrosine kinase and formation of protein complexes containing p72syk and Src family kinases in neutrophils spreading over fibrinogen.  J Immunol. 1997;  158 1902-1910
    PubMedGoogle Scholar
  • 67 Miller L A, Hong J J, Kinch M S, Harrison M L, Geahlen R L. The engagement of beta1 integrins on promonocytic cells promotes phosphorylation of Syk and formation of a protein complex containing Lyn and beta1 integrin.  Eur J Immunol. 1999;  29 1426-1434
    CrossrefPubMedGoogle Scholar
  • 68 Mocsai A, Zhou M, Meng F, Tybulewicz V L, Lowell C A. Syk is required for integrin signaling in neutrophils.  Immunity. 2002;  16 547-558
    CrossrefPubMedGoogle Scholar
  • 69 Vines C M, Potter J W, Xu Y et al.. Inhibition of beta 2 integrin receptor and Syk kinase signaling in monocytes by the Src family kinase Fgr.  Immunity. 2001;  15 507-519
    CrossrefPubMedGoogle Scholar
  • 70 Miranti C K, Leng L, Maschberger P, Brugge J S, Shattil S J. Identification of a novel integrin signaling pathway involving the kinase Syk and the guanine nucleotide exchange factor Vav1.  Curr Biol. 1998;  8 1289-1299
    CrossrefPubMedGoogle Scholar
  • 71 Obergfell A, Judd B A, del Pozo M A, Schwartz M A, Koretzky G A, Shattil S J. The molecular adapter SLP-76 relays signals from platelet integrin alphaIIbbeta3 to the actin cytoskeleton.  J Biol Chem. 2001;  276 5916-5923
    CrossrefPubMedGoogle Scholar
  • 72 Judd B A, Myung P S, Leng L et al.. Hematopoietic reconstitution of SLP-76 corrects hemostasis and platelet signaling through alpha IIb beta 3 and collagen receptors.  Proc Natl Acad Sci USA. 2000;  97 12056-12061
    CrossrefPubMedGoogle Scholar
  • 73 Wonerow P, Obergfell A, Wilde J I et al.. Differential role of glycolipid-enriched membrane domains in glycoprotein VI- and integrin-mediated phospholipase Cgamma2 regulation in platelets.  Biochem J. 2002;  364 755-765
    CrossrefPubMedGoogle Scholar
  • 74 Clark E A, Brugge J S. Integrins and signal transduction pathways: the road taken.  Science. 1995;  268 233-239
    PubMedGoogle Scholar
  • 75 Clark E A, Shattil S J, Brugge J S. Regulation of protein tyrosine kinases in platelets.  Trends Biochem Sci. 1994;  19 464-469
    CrossrefPubMedGoogle Scholar
  • 76 Keely P J, Parise L V. The alpha2beta1 integrin is a necessary co-receptor for collagen-induced activation of Syk and the subsequent phosphorylation of phospholipase Cgamma2 in platelets.  J Biol Chem. 1996;  271 26668-26676
    CrossrefPubMedGoogle Scholar
  • 77 Sarkar S, Rooney M M, Lord S T. Activation of integrin-beta3-associated syk in platelets.  Biochem J. 1999;  338 677-680
    CrossrefPubMedGoogle Scholar
  • 78 Law D A, Nannizzi-Alaimo L, Ministri K et al.. Genetic and pharmacological analyses of Syk function in alphaIIbbeta3 signaling in platelets.  Blood. 1999;  93 2645-2652
    PubMedGoogle Scholar
  • 79 Ron D, Chen C H, Caldwell J, Jamieson L, Orr E, Mochly-Rosen D. Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins.  Proc Natl Acad Sci USA. 1994;  91 839-843
    PubMedGoogle Scholar
  • 80 Mochly-Rosen D, Gordon A S. Anchoring proteins for protein kinase C: a means for isozyme selectivity.  FASEB J. 1998;  12 35-42
    PubMedGoogle Scholar
  • 81 Yarwood S J, Steele M R, Scotland G, Houslay M D, Bolger G B. The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform.  J Biol Chem. 1999;  274 14909-14917
    CrossrefPubMedGoogle Scholar
  • 82 Geijsen N, Spaargaren M, Raaijmakers J A, Lammers J W, Koenderman L, Coffer P J. Association of RACK1 and PKCbeta with the common beta-chain of the IL-5/IL-3/GM-CSF receptor.  Oncogene. 1999;  18 5126-5130
    CrossrefPubMedGoogle Scholar
  • 83 Rodriguez M M, Ron D, Touhara K, Chen C H, Mochly-Rosen D. RACK1, a protein kinase C anchoring protein, coordinates the binding of activated protein kinase C and select pleckstrin homology domains in vitro.  Biochemistry. 1999;  38 13787-13794
    CrossrefPubMedGoogle Scholar
  • 84 Buensuceso C S, Woodside D, Huff J L, Plopper G E, O'Toole T E. The WD protein Rack1 mediates protein kinase C and integrin-dependent cell migration.  J Cell Sci. 2001;  114 1691-1698
    PubMedGoogle Scholar
  • 85 Liliental J, Chang D D. Rack1, a receptor for activated protein kinase C, interacts with integrin beta subunit.  J Biol Chem. 1998;  273 2379-2383
    CrossrefPubMedGoogle Scholar
  • 86 Besson A, Wilson T L, Yong V W. The anchoring protein RACK1 links protein kinase Cepsilon to integrin beta chains. Requirements for adhesion and motility.  J Biol Chem. 2002;  277 22073-22084
    CrossrefPubMedGoogle Scholar
  • 87 Cox E A, Bennin D, Doan A T, O'Toole T, Huttenlocher A. RACK1 regulates integrin-mediated adhesion, protrusion, and chemotactic cell migration via its Src-binding site.  Mol Biol Cell. 2003;  14 658-669
    CrossrefPubMedGoogle Scholar
  • 88 Hannigan G E, Leung-Hagesteijn C, Fitz-Gibbon L et al.. Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase.  Nature. 1996;  379 91-96
    CrossrefPubMedGoogle Scholar
  • 89 Dedhar S, Williams B, Hannigan G. Integrin-linked kinase (ILK): a regulator of integrin and growth-factor signalling.  Trends Cell Biol. 1999;  9 319-323
    CrossrefPubMedGoogle Scholar
  • 90 Dedhar S. Cell-substrate interactions and signaling through ILK.  Curr Opin Cell Biol. 2000;  12 250-256
    CrossrefPubMedGoogle Scholar
  • 91 Wu C Y, Dedhar S. Integrin-linked kinase (ILK) and its interactors: a new paradigm for the coupling of extracellular matrix to actin cytoskeleton and signaling complexes.  J Cell Biol. 2001;  155 505-510
    CrossrefPubMedGoogle Scholar
  • 92 Pasquet J M, Noury M, Nurden A T. Evidence that the platelet integrin alphaIIb beta3 is regulated by the integrin-linked kinase, ILK, in a PI3-kinase dependent pathway.  Thromb Haemost. 2002;  88 115-122
    PubMedGoogle Scholar
  • 93 Yamaji S, Suzuki A, Kanamori H et al.. Possible role of ILK-affixin complex in integrin-cytoskeleton linkage during platelet aggregation.  Biochem Biophys Res Commun. 2002;  297 1324-1331
    CrossrefPubMedGoogle Scholar
  • 94 Yamaji S, Suzuki A, Sugiyama Y et al.. A novel integrin-linked kinase-binding protein, affixin, is involved in the early stage of cell-substrate interaction.  J Cell Biol. 2001;  153 1251-1264
    CrossrefPubMedGoogle Scholar
  • 95 Barry F A, Gibbins J M. Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI.  J Biol Chem. 2002;  277 12874-12878
    CrossrefPubMedGoogle Scholar
  • 96 Price M G. Skelemins: cytoskeletal proteins located at the periphery of M-discs in mammalian striated muscle.  J Cell Biol. 1987;  104 1325-1336
    CrossrefPubMedGoogle Scholar
  • 97 Reddy K B, Gascard P, Price M G, Negrescu E V, Fox J E. Identification of an interaction between the m-band protein skelemin and beta-integrin subunits. Colocalization of a skelemin-like protein with beta1- and beta3-integrins in non-muscle cells.  J Biol Chem. 1998;  273 35039-35047
    CrossrefPubMedGoogle Scholar
  • 98 Reddy K B, Bialkowska K, Fox J E. Dynamic modulation of cytoskeletal proteins linking integrins to signaling complexes in spreading cells. Role of skelemin in initial integrin-induced spreading.  J Biol Chem. 2001;  276 28300-28308
    CrossrefPubMedGoogle Scholar
  • 99 Djinovic-Carugo K, Gautel M, Ylanne J, Young P. The spectrin repeat: a structural platform for cytoskeletal protein assemblies.  FEBS Lett. 2002;  513 119-123
    CrossrefPubMedGoogle Scholar
  • 100 Goldmann W H. Kinetic determination of focal adhesion protein formation.  Biochem Biophys Res Commun. 2000;  271 553-557
    CrossrefPubMedGoogle Scholar
  • 101 Otey C A, Vasquez G B, Burridge K, Erickson B W. Mapping of the alpha-actinin binding site within the beta 1 integrin cytoplasmic domain.  J Biol Chem. 1993;  268 21193-21197
    PubMedGoogle Scholar
  • 102 Lyman S, Gilmore A, Burridge K, Gidwitz S, White II G C. Integrin-mediated activation of focal adhesion kinase is independent of focal adhesion formation or integrin activation. Studies with activated and inhibitory beta3 cytoplasmic domain mutants.  J Biol Chem. 1997;  272 22538-22547
    CrossrefPubMedGoogle Scholar
  • 103 Izaguirre G, Aguirre L, Hu Y P et al.. The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase.  J Biol Chem. 2001;  276 28676-28685
    CrossrefPubMedGoogle Scholar
  • 104 Stossel T P, Condeelis J, Cooley L et al.. Filamins as integrators of cell mechanics and signalling.  Nat Rev Mol Cell Biol. 2001;  2 138-145
    Google Scholar
  • 105 Gorlin J B, Yamin R, Egan S et al.. Human endothelial actin-binding protein (ABP-280, nonmuscle filamin): a molecular leaf spring.  J Cell Biol. 1990;  111 1089-1105
    CrossrefPubMedGoogle Scholar
  • 106 Pavalko F M, Otey C A, Burridge K. Identification of a filamin isoform enriched at the ends of stress fibers in chicken embryo fibroblasts.  J Cell Sci. 1989;  94 109-118
    PubMedGoogle Scholar
  • 107 Loo D T, Kanner S B, Aruffo A. Filamin binds to the cytoplasmic domain of the beta1-integrin. Identification of amino acids responsible for this interaction.  J Biol Chem. 1998;  273 23304-23312
    CrossrefPubMedGoogle Scholar
  • 108 Sharma C P, Ezzell R M, Arnaout M A. Direct interaction of filamin (ABP-280) with the beta 2-integrin subunit CD18.  J Immunol. 1995;  154 3461-3470
    PubMedGoogle Scholar
  • 109 Calderwood D A, Huttenlocher A, Kiosses W B et al.. Increased filamin binding to beta-integrin cytoplasmic domains inhibits cell migration.  Nat Cell Biol. 2001;  3 1060-1068
    CrossrefPubMedGoogle Scholar
  • 110 Williamson D, Pikovski I, Cranmer S L et al.. Interaction between platelet glycoprotein Ibα and filamin-1 is essential for glycoprotein Ib/IX receptor anchorage at high shear.  J Biol Chem. 2002;  277 2151-2159
    CrossrefPubMedGoogle Scholar
  • 111 Datta A, Huber F, Boettiger D. Phosphorylation of beta3 integrin controls ligand binding strength.  J Biol Chem. 2002;  277 3943-3949
    CrossrefPubMedGoogle Scholar
  • 112 Ling Y, Maile L A, Clemmons D R. Tyrosine phosphorylation of the beta3-subunit of the alphaVbeta3 integrin is required for membrane association of the tyrosine phosphatase SHP-2 and its further recruitment to the insulin-like growth factor I receptor.  Mol Endocrinol. 2003;  17 1824-1833
    CrossrefPubMedGoogle Scholar
  • 113 Heiser P W, Cowan K J, DeGuzman F R, Lowell C A, Law D A, Phillips D R. Identification of Fyn as the β3 tyrosine kinase that dynamically regulates αIIbβ3 function and irreversible platelet aggregation.  Blood. 2000;  96 811A
    PubMedGoogle Scholar
  • 114 Phillips D R, Prasad K S, Manganello J, Bao M, Nannizzi-Alaimo L. Integrin tyrosine phosphorylation in platelet signaling.  Curr Opin Cell Biol. 2001;  13 546-554
    CrossrefPubMedGoogle Scholar
  • 115 Cowan K J, Law D A, Phillips D R. Identification of shc as the primary protein binding to the tyrosine-phosphorylated beta 3 subunit of alpha IIbbeta 3 during outside-in integrin platelet signaling.  J Biol Chem. 2000;  275 36423-36429
    CrossrefPubMedGoogle Scholar
  • 116 Jenkins A L, Nannizzi-Alaimo L, Silver D et al.. Tyrosine phosphorylation of the beta3 cytoplasmic domain mediates integrin-cytoskeletal interactions.  J Biol Chem. 1998;  273 13878-13885
    CrossrefPubMedGoogle Scholar
  • 117 Sajid M, Hu Z, Lele M, Stouffer G A. Protein complexes involving alpha v beta 3 integrins, nonmuscle myosin heavy chain-A, and focal adhesion kinase from in thrombospondin-treated smooth muscle cells.  J Investig Med. 2000;  48 190-197
    PubMedGoogle Scholar
  • 118 Law D A, DeGuzman F R, Heiser P, Ministri-Madrid K, Killeen N, Phillips D R. Integrin cytoplasmic tyrosine motif is required for outside-in alphaIIbbeta3 signalling and platelet function.  Nature. 1999;  401 808-811
    CrossrefPubMedGoogle Scholar
  • 119 Shock D D, Naik U P, Brittain J E, Alahari S K, Sondek J, Parise L V. Calcium-dependent properties of CIB binding to the integrin alphaIIb cytoplasmic domain and translocation to the platelet cytoskeleton.  Biochem J. 1999;  342 729-735
    CrossrefPubMedGoogle Scholar
  • 120 Naik U P, Patel P M, Parise L V. Identification of a novel calcium-binding protein that interacts with the integrin alphaIIb cytoplasmic domain.  J Biol Chem. 1997;  272 4651-4654
    CrossrefPubMedGoogle Scholar
  • 121 Vallar L, Melchior C, Plancon S et al.. Divalent cations differentially regulate integrin alphaIIb cytoplasmic tail binding to beta3 and to calcium- and integrin-binding protein.  J Biol Chem. 1999;  274 17257-17266
    CrossrefPubMedGoogle Scholar
  • 122 Barry W T, Boudignon-Proudhon C, Shock D D et al.. Molecular basis of CIB binding to the integrin alpha IIb cytoplasmic domain.  J Biol Chem. 2002;  277 28877-28883
    CrossrefPubMedGoogle Scholar
  • 123 Tsuboi S. Calcium integrin-binding protein activates platelet integrin alpha IIbbeta 3.  J Biol Chem. 2002;  277 1919-1923
    CrossrefPubMedGoogle Scholar
  • 124 Naik U P, Naik M U. Association of CIB with GPIIb/IIIa during outside-in signaling is required for platelet spreading on fibrinogen.  Blood. 2003;  102 1355-1362
    CrossrefPubMedGoogle Scholar
  • 125 Naik M U, Naik U P. Calcium- and integrin-binding protein regulates focal adhesion kinase activity during platelet spreading on immobilized fibrinogen.  Blood. 2003;  102 3529-3636
    PubMedGoogle Scholar
  • 126 Kauselmann G, Weiler M, Wulff P et al.. The polo-like protein kinases Fnk and Snk associate with a Ca(2+)-and integrin-binding protein and are regulated dynamically with synaptic plasticity.  EMBO J. 1999;  18 5528-5539
    CrossrefPubMedGoogle Scholar
  • 127 Holtrich U, Wolf G, Yuan J et al.. Adhesion induced expression of the serine/threonine kinase Fnk in human macrophages.  Oncogene. 2000;  19 4832-4839
    CrossrefPubMedGoogle Scholar
  • 128 Ma S, Liu M A, Yuan Y L, Erikson R L. The serum-inducible protein kinase Snk is a G1 phase polo-like kinase that is inhibited by the calcium- and integrin-binding protein CIB.  Mol Cancer Res. 2003;  1 376-384
    PubMedGoogle Scholar
  • 129 Stabler S M, Ostrowski L L, Janicki S M, Monteiro M J. A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer’s disease presenilin 2 protein.  J Cell Biol. 1999;  145 1277-1292
    CrossrefPubMedGoogle Scholar
  • 130 Whitehouse C, Chambers J, Howe K, Cobourne M, Sharpe P, Solomon E. NBR1 interacts with fasciculation and elongation protein zeta-1 (FEZ1) and calcium and integrin binding protein (CIB) and shows developmentally restricted expression in the neural tube.  Eur J Biochem. 2002;  269 538-545
    CrossrefPubMedGoogle Scholar
  • 131 Fang X, Chen C, Wang Q, Gu J, Chi C. The interaction of the calcium- and integrin-binding protein (CIBP) with the coagulation factor VIII.  Thromb Res. 2001;  102 177-185
    CrossrefPubMedGoogle Scholar
  • 132 Haataja L, Kaartinen V, Groffen J, Heisterkamp N. The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading.  J Biol Chem. 2002;  277 8321-8328
    CrossrefPubMedGoogle Scholar
  • 133 Kato A, Kawamata N, Tamayose K et al.. Ancient ubiquitous protein 1 binds to the conserved membrane-proximal sequence of the cytoplasmic tail of the integrin alpha subunits that plays a crucial role in the inside-out signaling of alpha IIbbeta 3.  J Biol Chem. 2002;  277 28934-28941
    CrossrefPubMedGoogle Scholar
  • 134 Fujimoto T T, Katsutani S, Shimomura T, Fujimura K. Thrombospondin-bound integrin-associated protein (CD47) physically and functionally modifies Integrin alphaIIbbeta3 by its extracellular domain.  J Biol Chem. 2003;  278 26655-26665
    CrossrefPubMedGoogle Scholar
  • 135 Lindberg F P, Bullard D C, Caver T E, Gresham H D, Beaudet A L, Brown E J. Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice.  Science. 1996;  274 795-798
    CrossrefPubMedGoogle Scholar
  • 136 Dorahy D J, Berndt M C, Shafren D R, Burns G F. CD36 is spatially associated with glycoprotein IIb-IIIa (alpha IIb beta 3) on the surface of resting platelets.  Biochem Biophys Res Commun. 1996;  218 575-581
    CrossrefPubMedGoogle Scholar
  • 137 Miao W M, Vasile E, Lane W S, Lawler J. CD36 associates with CD9 and integrins on human blood platelets.  Blood. 2001;  97 1689-1696
    CrossrefPubMedGoogle Scholar
  • 138 Yamamoto N, Akamatsu N, Yamazaki H, Tanoue K. Normal aggregations of glycoprotein IV (CD36)-deficient platelets from seven healthy Japanese donors.  Br J Haematol. 1992;  81 86-92
    CrossrefPubMedGoogle Scholar
  • 139 Boucheix C, Rubinstein E. Tetraspanins.  Cell Mol Life Sci. 2001;  58 1189-1205
    PubMedGoogle Scholar
  • 140 Berditchevski F. Complexes of tetraspanins with integrins: more than meets the eye.  J Cell Sci. 2001;  114 4143-4151
    PubMedGoogle Scholar
  • 141 Yauch R L, Kazarov A R, Desai B, Lee R T, Hemler M E. Direct extracellular contact between integrin alpha(3)beta(1) and TM4SF protein CD151.  J Biol Chem. 2000;  275 9230-9238
    CrossrefPubMedGoogle Scholar
  • 142 Fitter S, Sincock P M, Jolliffe C N, Ashman L K. Transmembrane 4 superfamily protein CD151 (PETA-3) associates with beta 1 and alpha IIb beta 3 integrins in haemopoietic cell lines and modulates cell-cell adhesion.  Biochem J. 1999;  338 61-70
    CrossrefPubMedGoogle Scholar
  • 143 Berditchevski F, Odintsova E. Characterization of integrin-tetraspanin adhesion complexes: role of tetraspanins in integrin signaling.  J Cell Biol. 1999;  146 477-492
    CrossrefPubMedGoogle Scholar
  • 144 Sawada S, Yoshimoto M, Odintsova E, Hotchin N A, Berditchevski F. The tetraspanin CD151 functions as a negative regulator in the adhesion-dependent activation of Ras.  J Biol Chem. 2003;  278 26323-26326
    CrossrefPubMedGoogle Scholar
  • 145 Slupsky J R, Seehafer J G, Tang S C, Masellis-Smith A, Shaw A R. Evidence that monoclonal antibodies against CD9 antigen induce specific association between CD9 and the platelet glycoprotein IIb-IIIa complex.  J Biol Chem. 1989;  264 12289-12293
    PubMedGoogle Scholar
  • 146 Indig F E, Diaz-Gonzalez F, Ginsberg M H. Analysis of the tetraspanin CD9-integrin αIIbβ3 (GPIIb-IIIa) complex in platelet membranes and transfected cells.  Biochem J. 1997;  327 291-298
    PubMedGoogle Scholar
  • 147 Slupsky J R, Kamiguti A S, Rhodes N P, Cawley J C, Shaw A R, Zuzel M. The platelet antigens CD9, CD42 and integrin alpha IIb beta IIIa can be topographically associated and transduce functionally similar signals.  Eur J Biochem. 1997;  244 168-175
    CrossrefPubMedGoogle Scholar
  • 148 Israels S J, McMillan-Ward E M, Easton J, Robertson C, McNicol A. CD63 associates with the alphaIIb beta3 integrin-CD9 complex on the surface of activated platelets.  Thromb Haemost. 2001;  85 134-141
    PubMedGoogle Scholar
  • 149 Fenczik C A, Sethi T, Ramos J W, Hughes P E, Ginsberg M H. Complementation of dominant suppression implicates CD98 in integrin activation.  Nature. 1997;  390 81-85
    CrossrefPubMedGoogle Scholar
  • 150 Fenczik C A, Zent R, Dellos M et al.. Distinct domains of CD98hc regulate integrins and amino acid transport.  J Biol Chem. 2001;  276 8746-8752
    CrossrefPubMedGoogle Scholar
  • 151 Zent R, Fenczik C A, Calderwood D A, Liu S, Dellos M, Ginsberg M H. Class- and splice variant-specific association of CD98 with integrin beta cytoplasmic domains.  J Biol Chem. 2000;  275 5059-5064
    CrossrefPubMedGoogle Scholar
  • 152 Kolesnikova T V, Mannion B A, Berditchevski F, Hemler M E. Beta1 integrins show specific association with CD98 protein in low density membranes.  BMC Biochem. 2001;  2 10
    CrossrefPubMedGoogle Scholar
  • 153 Miyamoto Y J, Mitchell J S, McIntyre B W. Physical association and functional interaction between beta1 integrin and CD98 on human T lymphocytes.  Mol Immunol. 2003;  39 739-751
    CrossrefPubMedGoogle Scholar
  • 154 Otey C A, Pavalko F M, Burridge K. An interaction between alpha-actinin and the beta 1 integrin subunit in vitro.  J Cell Biol. 1990;  111 721-729
    CrossrefPubMedGoogle Scholar

 Dr.
Sanford J Shattil

Department of Medicines, University of California San Diego, Leichtag Biomedical Research Building

9500 Gilman Drive, MC 0726

La Jolla, CA 92093

Email: shattil@scripps.edu