Post-Ligand Binding Events: Outside-In Signaling Through the Integrins

  • Frank S. David
  • Andreas Kern
  • Eugene E. Marcantonio


Though first identified based on their interaction with extracellular matrix (ECM) molecules, integrins clearly function as more than simply mechanical linkages between cells and the ECM. The earliest molecular biological inquiries into integrin function, in which many of the different a and 13 subunits were cloned and characterized, revealed that large numbers of different heterodimers are capable of recognizing the same ligand. This observation alone suggests that either there is a large amount of redundancy in the integrin family or different integrins which bind the same ligand can be distinguished on the basis of the intracellular signals they generate.


Focal Adhesion Kinase Focal Adhesion Cytoplasmic Domain Focal Contact Integrin Function 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lafrenie RM, Yamada KM. Integrin-dependent signal transduction. J Cell Biochem 1996; 61: 543–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Schwartz MA, Schaller MD, Ginsberg MH. Integrins: emerging paradigms of signal transduction. Annu Rev Cell Dev Biol 1995; 11: 549–99.PubMedCrossRefGoogle Scholar
  3. 3.
    Jokusch BM, Bubeck P, Giehl K et al. The molecular architecture of focal adhesions. Annu Rev Cell Dev Biol 1995; 11: 379–416.CrossRefGoogle Scholar
  4. 4.
    Smilenov L, Briesewitz R, Marcantonio EE. Integrin 131 cytoplasmic domain effects revealed by lysophosphatidic acid treatment. Mol Biol Cell 1994; 5: 1215–23.PubMedGoogle Scholar
  5. 5.
    Salmivirta M, Jalkanen M. Syndecan familiy of cell surface proteoglycans: developmentally regulated receptors for extracellular effector molecules. Experientia 1995; 51: 863–72.PubMedCrossRefGoogle Scholar
  6. 6.
    Woods A, Couchman JR, Johannson S et al. Adhesion and cytoskeletal organization of fibroblasts in response to fibronectin fragments. EMBO J 1986; 5: 665–70.PubMedGoogle Scholar
  7. 7.
    Woods A, McCarthy JB, Furcht LT et al. A synthetic peptide from the COOH-terminal heparin binding domain of fibronectin promotes focal adhesion formation. Mol Biol Cell 1993; 4: 605–13.PubMedGoogle Scholar
  8. 8.
    Woods A, Couchman JR. Protein kinase C involvement in focal adhesion formation. J Cell Sci 1992; 101: 277–90.PubMedGoogle Scholar
  9. 9.
    Woods A, Couchman JR. Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component. Mol Biol Cell 1994; 5: 183–92.PubMedGoogle Scholar
  10. 10.
    Baciu PC, Goetinck PF. Protein kinase C regulates the recruitment of syndecan-4 into focal contacts. Mol Biol Cell 1995; 6: 1503–13.PubMedGoogle Scholar
  11. 11.
    Brown E, Hooper L, Ho T et al. Integrinassociated protein: a 50-kDa plasma membrane antigen physically and functionally associated with integrins. J Cell Biol 1990; 111: 2785–94.PubMedCrossRefGoogle Scholar
  12. 12.
    Gao AG, Lindberg FP, Finn MB et al. Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin. J Biol Chem 1996; 271: 21–4.PubMedCrossRefGoogle Scholar
  13. 13.
    Guadagno TM, Assoian RK. G1/S control of anchorage-independent growth in the fibroblast cell cycle. J Cell Biol 1991; 115: 1419–25.PubMedCrossRefGoogle Scholar
  14. 14.
    Han EKH, Guadagno TM, Dalton SL et al. A cell cycle and mutational analysis of anchorage-independent growth: cell adhesion and TGF-ß1 control G 1 /S transit specifically. J Cell Biol 1993; 122: 461–71.PubMedCrossRefGoogle Scholar
  15. 15.
    Zhu X, Ohtsubo M, Böhmer RM et al. Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclinE-cdk2, and phosphorylation of the retinoblastoma protein. J Cell Biol 1996; 133: 391–403.PubMedCrossRefGoogle Scholar
  16. 16.
    Fang F, Orend G, Watanabe N et al. Dependence of cyclin E-cdk2 kinase activity on cell anchorage. Science (Wash. DC) 1996; 271: 499–502.CrossRefGoogle Scholar
  17. 17.
    von der Mark K, Öcalan M. Antagonistic effects of laminin and fibronectin on the expression of the myogenic phenotype. Differentiation 1989; 40: 150–57.PubMedCrossRefGoogle Scholar
  18. 18.
    Sastry SK, Lakonishok M, Thomas DA et al. Integrin a subunit ratios, cytoplasmic domains and growth factor synergy regulate muscle proliferation and differentiation. J Cell Biol 1996; 133: 169–84.PubMedCrossRefGoogle Scholar
  19. 19.
    Kubota W, Kleinman HK, Martin GR et al. Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures. J Cell Biol 1988; 107: 1589–98.PubMedCrossRefGoogle Scholar
  20. 20.
    Meredith JE, Fazeli B, Schwartz MA. The extracellular matrix as a cell survival factor. Mol Biol Cell 1993; 4: 953–61.PubMedGoogle Scholar
  21. 21.
    Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 1994; 124: 619–26.PubMedCrossRefGoogle Scholar
  22. 22.
    Pullan S, Wilson J, Metcalfe A et al. Requirement of basement membrane for the suppression of programmed cell death in mammary epithelium. J Cell Sci 1996; 109: 631–42.PubMedGoogle Scholar
  23. 23.
    Zhang Z, Vuori K, Reed JC et al. The 0131 integrin supports survival of cells on fibronectin and up-regulates Bcl-2 expression. Proc Natl Acad Sci USA 1995; 92: 6161–65.PubMedCrossRefGoogle Scholar
  24. 24.
    Chen Q, Kinch MS, Lin TH et al. Integrinmediated cell adhesion activates mitogenactivated protein kinases. J Biol Chem 1994; 269: 26602–05.PubMedGoogle Scholar
  25. 25.
    Zhu X, Assoian RK. Integrin-dependent activation of MAP kinase: a link to shape-dependent cell proliferation. Mol Biol Cell 1995; 6: 273–82.PubMedGoogle Scholar
  26. 26.
    Chen Q, Lin TH, Der q et al. Integrinmediated activation of Mitogen-activated Protein (MAP) or Extracellular Signal-related Kinase Kinase (MEK) and Kinase is independent of Ras. J Biol Chem 1996; 271: 18122–27.PubMedCrossRefGoogle Scholar
  27. 27.
    Clark EA, Hynes RO. Ras activation is necessary for integrin-mediated activation of Extracellular Signal-regulated Kinase 2 and cytosolic Phospholipase A2 but not for cytoskeletal organization. J Biol Chem 1996; 271: 14814–18.PubMedCrossRefGoogle Scholar
  28. 28.
    Filardo EJ, Cheresh DA. A ß turn in the cytoplasmic tail of the integrin av subunit influences conformation and ligand binding of avß3. J Biol Chem 1994; 269: 4641–47.PubMedGoogle Scholar
  29. 29.
    O’Toole TE, Mandelmann D, Forsyth J et al. Modulation of the affinity of integrin alIb133 (GPIIb-IIIa) by the cytoplasmic domain of ulib. Science (Wash. DC) 1991; 254: 845–47.CrossRefGoogle Scholar
  30. 30.
    Kassner PD, Alon R, Springer TA et al. Specialized functional properties of the integrin a4 cytoplasmic domain. Mol Biol Cell 1995; 6: 661–74.PubMedGoogle Scholar
  31. 31.
    Hughes PE, Diaz-Gonzalez F, Leong L et al. Breaking the integrin hinge. J Biol Chem 1996; 271: 6571–74.PubMedCrossRefGoogle Scholar
  32. 32.
    Chan BMC, Kassner PD, Schiro JA et al. Distinct cellular functions mediated by different VLA integrin a subunit cytoplasmic domains. Cell 1992; 68: 1051–60.PubMedCrossRefGoogle Scholar
  33. 33.
    Kawaguchi S, Bergelson JM, Finberg RW et al. Integrin a2 cytoplasmic domain deletion effects: loss of adhesive activity parallels ligand-independent recruitment into focal adhesions. Mol Biol Cell 1994; 5: 977–88.PubMedGoogle Scholar
  34. 34.
    Briesewitz R, Kern A, Marcantonio FE. Ligand-dependent and -independent integrin focal contact localization: the role of the a chain cytoplasmic domain. Mol Biol Cell 1993; 4: 593–604.PubMedGoogle Scholar
  35. 35.
    Ylänne J, Chen Y, O’Toole TE et al. Distinct functions of integrin a and ß subunit cytoplasmic domains in cell spreading and formation of focal adhesions. J Cell Biol 1993; 122: 223–33.PubMedCrossRefGoogle Scholar
  36. 36.
    LaFlamme SE, Akiyama SK, Yamada KM. Regulation of fibronectin receptor distribution. J Cell Biol 1992; 117: 437–47.PubMedCrossRefGoogle Scholar
  37. 37.
    Geiger B, Salomon D, Takeichi M et al. A chimeric N-cadherin/131 integrin receptor which localizes to both cell-cell and cell-matrix adhesions. J Cell Sci 1992; 103: 943–5 I.Google Scholar
  38. 38.
    Akiyama SK, Yamada SS, Yamada KM et al. Transmembrane signal transduction by integrin cytoplasmic domains expressed in single-subunit chimeras. J Biol Chem 1994; 269: 15961–64.PubMedGoogle Scholar
  39. 39.
    Lukashev ME, Sheppard D, Pytela R. Disruption of integrin function and induction of tyrosine phsophorylation by the autonomously expressed 131 cytoplasmic domain. J Biol Chem 1994; 269: 18311–14.PubMedGoogle Scholar
  40. 40.
    LaFlamme SE, Thomas LA, Yamada SS et al. Single subunit chimeric integrins as mimics and inhibitors of endogenous integrin functions in receptor localization, cell spreading and migration, and matrix assembly. J Cell Biol 1994; 126: 1287–98.PubMedCrossRefGoogle Scholar
  41. 41.
    Solowska J, Guan JL, Marcantonio EE et al. Expression of normal and mutant avian integrin subunits in rodent cells. J Cell Biol 1989; 109: 853–61.PubMedCrossRefGoogle Scholar
  42. 42.
    Marcantonio EE, Guan JL, Trevithick JE et al. Mapping of the functional determinants of the integrin 131 cytoplasmic domain by site-directed mutagenesis. Cell Reg 1990; 1: 597–604.Google Scholar
  43. 43.
    Hayashi Y, Haimovich B, Reszka A et al. Expression and function of chicken 131 subunit and its cytoplasmic domain mutants in mouse NIH 3T3 cells. J Cell Biol 1990; 110: 175–84.PubMedCrossRefGoogle Scholar
  44. 44.
    Reszka AA, Hayashi Y, Horwitz AF. Identification of amino acid sequences in the integrin 131 cytoplasmic domain implicated in cytoskeletal association. J Cell Biol 1992; 117: 1321–1330.PubMedCrossRefGoogle Scholar
  45. 45.
    Chen YP, O’Toole TE, Ylänne J et al. A point mutation in the integrin f33 cytoplasmic domain (S752->P) impairs bidirectional signaling through allbß3 (platelet glycoprotein IIb-IIIa). Blood 1994; 84: 1857–65.PubMedGoogle Scholar
  46. 46.
    O’Toole TE, Ylänne J, Culley BM. Regula- tion of integrin affinity states through an NPXY motif in the ß subunit cytoplasmic domain. J Biol Chem 1995; 270: 8553–58.PubMedCrossRefGoogle Scholar
  47. 47.
    Hughes PE, O’Toole TE, Ylänne J et al. The conserved membrane-proximal region of an integrin cytoplasmic domain specifies ligand binding affinity. J Biol Chem 1995; 270: 12411–17.PubMedCrossRefGoogle Scholar
  48. 48.
    Otey CA, Vasquez GB, Burridge K et al. Mapping of the a-actinin binding site within the f31 integrin cytoplasmic domain. J Biol Chem 1993; 268: 21193–97.PubMedGoogle Scholar
  49. 49.
    Schaller MD, Otey CA, Hildebrand JD et al. Focal adhesion kinase and paxillin bind to peptides mimicking ß integrin cytoplasmic domains. J Cell Biol 1995; 130: 1181–87.PubMedCrossRefGoogle Scholar
  50. 50.
    Shattil SJ, O’Toole TE, Eigenthaler M et al. (33-endonexin, a novel polypeptide that interacts specifically with the cytoplasmic tail of the integrin (33 subunit. J Cell Biol 1995; 131: 807–16.Google Scholar
  51. 51.
    Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbons L et al. Regulation of cell adhesion and anchorage-dependent growth by a new 131-integrin-linked protein-kinase. Nature (Lond.) 1996; 379: 91–96.CrossRefGoogle Scholar
  52. 52.
    Kolanus W, Nagel W, Schiller B et al. aLß2 integrin/LFA-1 binding to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory molecule. Cell 1996; 86: 233–42.PubMedCrossRefGoogle Scholar
  53. 53.
    Briesewitz R, Kern A, Marcantonio EE. Assembly and function of integrin receptors is dependent on opposing a and ß cytoplasmic domains. Mol Biol Cell 1995; 6: 997–1010.PubMedGoogle Scholar
  54. 54.
    Huang MM, Lipfert L, Cunningham M et al. Adhesive ligand binding to integrin allb(33 stimulates tyrosine phosphorylation of novel protein substrates before phosphorylation of pp125FAK. J Cell Biol 1993; 122: 473–83.PubMedCrossRefGoogle Scholar
  55. 55.
    Heldin CH. Dimerization of cell surface receptors in signal transduction. Cell 1995; 80: 213–23.PubMedCrossRefGoogle Scholar
  56. 56.
    Miyamoto S, Akiyama SK, Yamada KM. Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science (Wash. DC) 1995a; 267: 883–85.CrossRefGoogle Scholar
  57. 57.
    Miyamoto S, Teramoto H, Coso OA et al. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol 1995b; 131: 791–805.PubMedCrossRefGoogle Scholar
  58. 58.
    Schlaepfer DD, Hanks SK, Hunter T et al. Integrin-mediated signal transduction by GRB2 binding to focal adhesion kinase. Nature (Lond.) 1994; 372: 786–91.Google Scholar
  59. 59.
    Frisch SM, Vuori K, Ruoslahti E et al. Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 1996; 134: 793–99.PubMedCrossRefGoogle Scholar
  60. 60.
    Ilic D, Furuta Y, Kanazawa S et al. Reduced motility and enhanced focal adhesion contact formation in cells from FAKdefiecient mice. Nature (Lond.) 1995; 377: 539–44.CrossRefGoogle Scholar
  61. 61.
    Bonfini L, Migliaccio E, Pelicci G et al. Not all she’s roads lead to ras. TIBS 1996; 21: 257–61.PubMedGoogle Scholar
  62. 62.
    Kern A, Briesewitz R, Bank I et al. The role of the I domain in ligand binding of the human integrin al (31. J Biol Chem 1994; 269: 22811–16.PubMedGoogle Scholar
  63. 63.
    Rubinstein E, LeNaour F, Billard M et al. CD9 antigen is an accessory subunit of the VLA integrin complexes. Eur J Immunol 1994; 24: 3003–13.CrossRefGoogle Scholar
  64. 64.
    Berditchevski F, Bazzoni G, Hemler ME. Specific association of CD63 with the VLA-3 and VLA-6 integrins. J Biol Chem 1995; 270: 17784–90.PubMedCrossRefGoogle Scholar
  65. 65.
    Berditchevski F, Zutter MM, Hemler ME. Characterization of novel complexes on the cell surface between integrins and proteins with 4 transmembrane domains (TM4 proteins). Mol Biol Cell 1996; 7: 193–207.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1997

Authors and Affiliations

  • Frank S. David
  • Andreas Kern
  • Eugene E. Marcantonio

There are no affiliations available

Personalised recommendations