Trends in Cell Biology
Volume 14, Issue 12, December 2004, Pages 678-686
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Integrins: versatile integrators of extracellular signals

https://doi.org/10.1016/j.tcb.2004.10.005Get rights and content

Extracellular matrix (ECM) molecules and growth factors have a crucial role in the signalling that controls cell behaviour during development. Integrins, which are cell-surface receptors for ECM molecules, and growth factor receptors cooperate with each other to regulate this signalling by several mechanisms. In particular, direct interactions between the integrin and growth factor receptors themselves, which often occur within a single macromolecular complex, amplify signalling by mechanisms that include posttranslational modifications and integrin shape changes that are related to activation. As a result, growth factor concentrations in the physiological range, which are too low to initiate signalling alone, do so in the presence of the ECM, enabling integrins to control the time and space of growth factor signalling.

Section snippets

Regulation by phosphorylation

Evidence for the direct potentiation of growth factor receptor signalling by integrins comes from elegant studies that have examined the interaction between αvβ3 and the epidermal growth factor receptor (EGFR) on human endothelial cells. Integrin-mediated adhesion to the ECM leads to an increase in phosphorylation of four tyrosine residues on the EGFR, a process that requires Src and the adaptor protein p130Cas. The level of EGFR phosphorylation mediated by integrins is lower than that observed

Regulation by expression levels

Just as integrins increase the expression of growth factor receptors, growth factor signalling has been shown to increase the expression of integrins in different types of cell, thereby providing a mechanism for regulating cell behaviour by altering the balance of different integrins. For example, angiogenic growth factors such as FGF-2 increase the expression of several different integrins on the surface of endothelial cells [18], and synergistic effects are observed when cells are grown in

Integrin activation: a mechanism to integrate signalling pathways?

We have highlighted two mechanisms by which growth factor receptors interact directly with integrins: phosphorylation of the cytoplasmic domain of integrin β4 by the EGFR in keratinocytes, and activation of the αv and α6 integrins in oligodendrocytes and endothelial cells. These mechanisms are particularly interesting for two reasons. First, they emphasize that interactions between integrins and growth factor receptors in the membrane can be reciprocal and bidirectional. Second, the fact that

Integrin activation and lipid-raft microdomains

Notably, the interactions between α6β4 and the EGFR in keratinocytes [28], and those between α6β1 and the PDGF-α receptor in oligodendrocytes [9], occur in lipid-raft microdomains. These are regions of membrane that are rich in cholesterol and glycosphingolipids [46], with the relative concentration of glycosylphosphatidylinositol-linked cell-surface molecules and intracellular signalling molecules including the Src family kinases discussed above [47]. These rafts can be isolated by virtue of

Concluding remarks

In summary, we have described how reciprocal and bidirectional interactions between integrins and growth factor receptors are important in regulating signalling from both receptors. In particular, we have shown how integrin activation by growth factors provides a simple integrative mechanism that can generate temporal and spatial control of growth factor signalling during development.

It should be noted that a model in which integrin activation and affinity modulation have central roles provides

Acknowledgements

We are funded by grants from the Wellcome Trust and the Multiple Sclerosis Society of Great Britain and Northern Ireland (to C.ff-C.), and by a National Multiple Sclerosis Society Career Transition fellowship that follows on from a National Institutes of Health postdoctoral fellowship (to H.C.). We are grateful to the anonymous referees of the manuscript for their helpful comments.

References (90)

  • C.V. Carman et al.

    Integrin avidity regulation: are changes in affinity and conformation underemphasized?

    Curr. Opin. Cell Biol.

    (2003)
  • T.V. Byzova

    A mechanism for modulation of cellular responses to VEGF: activation of the integrins

    Mol. Cell

    (2000)
  • N. Pampori

    Mechanisms and consequences of affinity modulation of integrin αVβ3 detected with a novel patch-engineered monovalent ligand

    J. Biol. Chem.

    (1999)
  • P. van Heyningen

    Control of progenitor cell number by mitogen supply and demand

    Curr. Biol.

    (2001)
  • D.A. Brown et al.

    Structure and function of sphingolipid- and cholesterol-rich membrane rafts

    J. Biol. Chem.

    (2000)
  • S. Munro

    Lipid rafts: elusive or illusive?

    Cell

    (2003)
  • P.W. Janes

    The role of lipid rafts in T cell antigen receptor (TCR) signalling

    Semin. Immunol.

    (2000)
  • J. Huai et al.

    An ephrin-A-dependent signaling pathway controls integrin function and is linked to the tyrosine phosphorylation of a 120-kDa protein

    J. Biol. Chem.

    (2001)
  • J. Chen

    The α2 integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis

    Am. J. Pathol.

    (2002)
  • D. Cosgrove

    Integrin α1β1 and transforming growth factor-β1 play distinct roles in Alport glomerular pathogenesis and serve as dual targets for metabolic therapy

    Am. J. Pathol.

    (2000)
  • U. Muller

    Integrin α8β1 is critically important for epithelial-mesenchymal interactions during kidney morphogenesis

    Cell

    (1997)
  • T.C. Klinowska

    Epithelial development and differentiation in the mammary gland is not dependent on α3 or α6 integrin subunits

    Dev. Biol.

    (2001)
  • H. Gardner

    Deletion of integrin α1 by homologous recombination permits normal murine development but gives rise to a specific deficit in cell adhesion

    Dev. Biol.

    (1996)
  • B.L. Bader

    Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all αv integrins

    Cell

    (1998)
  • A.G. Arroyo

    Differential requirements for α4 integrins during fetal and adult hematopoiesis

    Cell

    (1996)
  • S.C. Previtali

    Schwann cells synthesize α7β1 integrin which is dispensable for peripheral nerve development and myelination

    Mol. Cell. Neurosci.

    (2003)
  • H. Haack et al.

    Integrin receptors are required for cell survival and proliferation during development of the peripheral glial lineage

    Dev. Biol.

    (2001)
  • E.S. Anton

    Distinct functions of α3 and αv integrin receptors in neuronal migration and laminar organization of the cerebral cortex

    Neuron

    (1999)
  • D. Graus-Porta

    β1-class integrins regulate the development of laminae and folia in the cerebral and cerebellar cortex

    Neuron

    (2001)
  • M. Schwander

    β1 integrins regulate myoblast fusion and sarcomere assembly

    Dev. Cell

    (2003)
  • M.A. Schwartz et al.

    Networks and crosstalk: integrin signalling spreads

    Nat. Cell Biol.

    (2002)
  • F.G. Giancotti et al.

    Positional control of cell fate through joint integrin/receptor protein kinase signaling

    Annu. Rev. Cell Dev. Biol.

    (2003)
  • L. Moro

    Integrins induce activation of EGF receptor: role in MAP kinase induction and adhesion-dependent cell survival

    EMBO J.

    (1998)
  • R. Soldi

    Role of αvβ3 integrin in the activation of vascular endothelial growth factor receptor-2

    EMBO J.

    (1999)
  • M. Schneller

    αvβ3 integrin associates with activated insulin and PDGFβ receptors and potentiates the biological activity of PDGF

    EMBO J.

    (1997)
  • W. Baron

    The oligodendrocyte precursor mitogen PDGF stimulates proliferation by activation of αvβ3 integrins

    EMBO J.

    (2002)
  • A.N. Murphy

    Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation

    J. Cell. Physiol.

    (1993)
  • G. Bergers

    Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

    Nat. Cell Biol.

    (2000)
  • M.J. Reginato

    Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis

    Nat. Cell Biol.

    (2003)
  • J. Chung

    Integrin (α6β4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells

    J. Cell Biol.

    (2002)
  • F. Wang

    Reciprocal interactions between β1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • E. Cukierman

    Taking cell-matrix adhesions to the third dimension

    Science

    (2001)
  • S. Klein

    Basic fibroblast growth factor modulates integrin expression in microvascular endothelial cells

    Mol. Biol. Cell

    (1993)
  • G. Collo et al.

    Endothelial cell integrin α5β1 expression is modulated by cytokines and during migration in vitro

    J. Cell Sci.

    (1999)
  • G. Zambruno

    Transforming growth factor-β1 modulates β1 and β5 integrin receptors and induces the de novo expression of the αvβ6 heterodimer in normal human keratinocytes: implications for wound healing

    J. Cell Biol.

    (1995)
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