Integrins: Signalling and Disease


Cell‐surface adhesion molecules of the integrin family are not a passive glue, but rather are dynamic molecules that mediate the transfer of information across the membrane in both directions. Integrin‐mediated adhesion can be regulated in response to signals by clustering and conformational changes triggered at their cytoplasmic tails. Vice versa, integrins probe chemical and physical aspects of the extracellular environment and, in concert with growth factor receptors, activate signalling pathways in response. Integrin signalling controls cell survival, cell cycle progression, and differentiation, and the dynamic regulation of integrin‐mediated adhesion structures is critical for many forms of cell migration. Lastly, integrins contribute to the pathogenesis of a diverse array of acquired and hereditary diseases, and hence represent major targets for therapeutic intervention.

Key Concepts:

  • Integrins are heterodimeric transmembrane receptors that mediate cell adhesion to extracellular matrix proteins and other cells.

  • Integrins cluster in cell–matrix or cell–cell adhesions where they assemble large multiprotein complexes including actin‐binding proteins.

  • Integrin‐containing adhesions contain enzymes such as FAK, Src, Rac and many others as well as their upstream activators and downstream effectors allowing local activation of cellular signalling cascades.

  • Through a series of conformational changes in mechanoresponsive proteins, integrin‐containing adhesions provide mechanical coupling between the environment and the cytoskeletal network.

  • Signalling through various growth factor receptors is amplified in response to integrin‐mediated adhesion.

  • The ability of integrins to modulate cellular shape and cytoarchitecture in accordance with environmental stiffness as well as their role in a variety of biochemical signal transduction cascades underlies their critical function in cell proliferation, survival, differentiation and motility.

  • Defective integrin function underlies several human diseases.

  • Integrins represent potential drug targets and therapeutic strategies based on interference with integrin‐mediated adhesion have entered clinical trials.

Keywords: integrin; cell adhesion; signalling; disease

Figure 1.

Model for affinity modulation of integrins. (a) Schematic diagram depicting the arrangement of domains within an I domain‐containing integrin. The integrin is in an inactive bent conformation. (b, c) Ribbon diagrams depicting the bent inactive conformation of the extracellular portion of an integrin (b), and the extended conformation of the extracellular protein of an activated integrin (c). Black bar indicates 100 Å. Reprinted from Takagi et al., with permission from Elsevier.

Figure 2.

Sequence alignment of human integrin β subunit (a), and α subunit (b) cytoplasmic domains. Highly conserved amino acid residues are highlighted, and provided as a consensus below the alignments. Interacting proteins are indicated.

Figure 3.

(a–d) Modes of regulation of intracellular signal transduction cascades by integrins and crosstalk with other transmembrane receptors.



Assoian RK and Schwartz MA (2001) Coordinate signaling by integrins and receptor tyrosine kinases in the regulation of G1 phase cell‐cycle progression. Current Opinion in Genetics and Development 11: 48–53.

Bakker GJ, Eich C, Torreno‐Pina JA et al. (2012) Lateral mobility of individual integrin nanoclusters orchestrates the onset for leukocyte adhesion. Proceedings of the National Academy of Sciences of the USA 109: 4869–4874.

Bokel C and Brown N (2002) Integrins in development Moving on, responding to, and sticking to the extracellular matrix. Developmental Cell 3: 311–321.

Byron A, Humphries JD, Bass MD, Knight D and Humphries MJ (2011) Proteomic analysis of integrin adhesion complexes. Science Signaling 4(167): pt2.

Carman CV and Springer TA (2003) Integrin avidity regulation: are changes in affinity and conformation underemphasized? Current Opinion in Cell Biology 15: 547–556.

Colognato H, Baron W, Avellana‐Adalid V et al. (2002) CNS integrins switch growth factor signalling to promote target‐dependent survival. Nature Cell Biology 4: 833–841.

Friedland JC, Lee MH and Boettiger D (2009) Mechanically activated integrin switch controls alpha5beta1 function. Science 323: 642–644.

Frisch SM and Screaton RA (2001) Mechanisms of anoikis. Current Opinion in Cell Biology 13: 555–562.

Garcia‐Alvarez B, de Pereda JM, Calderwood DA et al. (2003) Structural determinants of integrin recognition by talin. Molecular Cell 11: 49–58.

Hemler ME (2005) Tetraspanin functions and associated microdomains. Nature Reviews Molecular Cell Biology 6: 801–811.

Horwitz AF (1997) Integrins and health. Scientific American 276: 46–53.

Howe AK, Aplin AE and Juliano RL (2002) Anchorage‐dependent Erk signaling – mechanisms and consequences. Current Opinion in Genetics and Development 12: 30–35.

Huveneers S and Danen EHJ (2009) Adhesion signaling – crosstalk between integrins, Src and Rho. Journal of Cell Science 122: 1059–1069.

Jiang G, Giannone G, Critchley DR, Fukumoto E and Sheetz MP (2003) Two‐piconewton slip bond between fibronectin and the cytoskeleton depends on talin. Nature 424: 334–337.

Law DA, DeGuzman FR, Heiser P et al. (1999) Integrin cytoplasmic tyrosine motif is required for outside‐in alphaIIbbeta3 signalling and platelet function. Nature 401: 808–811.

Liddington RH and Ginsberg MH (2002) Integrin activation takes shape. Journal of Cell Biology 158: 833–839.

Ling K, Doughman RL, Firestone AJ, Bunce MW and Anderson RA (2002) Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature 420: 89–93.

Matthews BD, Overby DR, Mannix R and Ingber DE (2006) Cellular adaptation to mechanical stress: role of integrins, Rho, cytoskeletal tension and mechanosensitive ion channels. Journal of Cell Science 119: 508–518.

Moore SW, Roca‐Cusachs P and Sheetz MP (2010) Stretchy proteins on stretchy substrates: the important elements of integrin‐mediated rigidity sensing. Developmental Cell 19: 194–206.

Moran‐Jones K, Ledger A and Naylor MJ (2012) Beta 1 integrin deletion enhances progression of prostate cancer in the TRAMP mouse model. Scientific Reports 2: 526.

Moser M, Legate KR, Zent R and Fassler R (2009) The tail of integrins, talin, and kindlins. Science 324: 895–899.

Poinat P, De Arcangelis A, Sookhareea S et al. (2002) A conserved interaction between beta1 integrin/PAT‐3 and Nck‐interacting kinase/MIG‐15 that mediates commissural axon navigation in C. elegans. Current Biology 12: 622–631.

Ramirez NE, Zhang ZH, Madamanchi A et al. (2011) The alpha(2)beta(1) integrin is a metastasis suppressor in mouse models and human cancer. Journal of Clinical Investigation 121: 226–237.

Schlaepfer DD and Hunter T (1998) Integrin signalling and tyrosine phosphorylation: just the FakS? Trends in Cell Biology 8: 151–157.

Schwartz MA (2001) Integrin signalling revisited. Trends in Cell Biology 11: 466–470.

Sheppard D (2004) Roles of alphav integrins in vascular biology and pulmonary pathology. Current Opinion in Cell Biology 16: 552–557.

Springer TA and Dustin ML (2012) Integrin inside‐out signaling and the immunological synapse. Current Opinion in Cell Biology 24: 107–115.

Tadokoro S, Shattil SJ, Eto K et al. (2003) Talin binding to integrin beta tails: a final common step in integrin activation. Science 302: 103–106.

Takagi J, Petre BM, Walz T and Springer TA (2002) Global conformational rearrangements in integrin extracellular domains in outside-in and inside‐out signaling. Cell 110: 599–611.

Tatler AL, John AE, Jolly L et al. (2011) Integrin αvβ5‐mediated TGF‐β activation by airway smooth muscle cells in asthma. Journal of Immunology 187: 6094–6107.

Ulbrich H, Eriksson EE and Lindbom L (2003) Leucocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease. Trends in Pharmacological Sciences 24: 640–647.

Wolfenson H, Lavelin I and Geiger B (2013) Dynamic regulation of the structure and functions of integrin adhesions. Developmental Cell 24: 447–458.

Zaidel‐Bar R, Itzkovitz S, Ma'ayan A, Iyengar R and Geiger B (2007) Functional atlas of the integrin adhesome. Nature Cell Biology 9: 858–867.

Further Reading

Cabodi S and Defilippi P (2005) The Essence of Integrin Signal Transduction: Assembly of Dynamic Scaffolds and Cross‐talk with Other Receptors. Georgetown, TX: Landes Bioscience.

Geiger B and Yamada KM (2011) Molecular architecture and function of matrix adhesions. Cold Spring Harbor Perspectives in Biology 3(5): 1–21.

Hynes RO (2002) Integrins: bidirectional, allosteric signalling machines. Cell 110: 673–687.

Katsumi A, Orr AW, Tzima E and Schwartz MA (2004) Structural basis of integrin regulation and signaling. Annual Review of Immunology 25: 619–647.

Wickstrom SA, Radovanac K and Fassler R (2011) Genetic analysis of integrin signaling. Cold Spring Harbor Perspectives in Biology 3(2): 1–22.

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Danen, Erik HJ(Sep 2013) Integrins: Signalling and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0004022.pub3]