Integrin regulation
Introduction
Integrins are composed of type I transmembrane α and β subunits, each with a large extracellular domain, a single-pass transmembrane (TM) domain and a small cytoplasmic domain, or tail. The main ligands for integrins are extracellular matrix adhesive proteins and cellular counter-receptors. High-affinity ligand binding requires integrins to become ‘activated’ by undergoing conformational changes regulated by inside-out signals. In turn, integrin ligation triggers outside-in signals that regulate, among other responses, cell motility and gene expression [1]. Recently, high-resolution structures of virtually the whole of the integrin αVβ3 extracellular domain and of the ligand-binding moiety of αIIbβ3 have been reported, a major advance (reviewed in [2, 3, 4, 5]). However, a complete understanding of bidirectional integrin signaling will require further studies of the experimentally less accessible TM and cytoplasmic domains, and of integrin structure in native membrane environments. Here we summarize recent progress in this area by discussing the role of integrin transmembrane and cytoplasmic domains in inside-out signaling; the relevance of integrin conformational changes and clustering to outside-in signaling; and the initiation of outside-in signaling by protein kinases and phosphatases bound directly to integrin cytoplasmic domains.
Section snippets
Regulation of integrins by inside-out signals
Integrin activation is widely used in physiology and abused in disease states. For example, it controls embryonic development, hemostasis, angiogenesis and tumor metastasis [1, 6, 7]. Many signaling pathways can regulate integrin activation; however, recent data has focused attention on talin as an indispensable mediator of this process.
Integrin β subunit cytoplasmic domains are required for integrin activation, whereas in most cases the α cytoplasmic domain plays a regulatory role. Changes in
Integrin regulation of outside-in signaling
Outside-in signaling intermediates include enzymes (e.g. FAK/c-Src complex, Ras and Rho GTPases) and adapters (e.g. Cas/Crk, paxillin) that assemble within dynamic adhesion structures, including focal complexes, focal adhesions and podosomes [35, 36]. Integrin signaling pathways collaborate with those activated by other plasma membrane receptors [37]. Even the smallest integrin-based assemblies visualized by immunofluorescence microscopy are likely to contain hundreds of integrin heterodimers
Conclusions and perspectives
There has been substantial recent progress in understanding how integrins are regulated and how they signal, thanks to structural analyses of integrin extracellular domains, characterization of proteins that interact with integrin cytoplasmic domains, and functional studies of gene-targeted mice. Nonetheless, it remains an open question how signals are propagated across the plasma membrane to and from the integrin extracellular and cytoplasmic domains. Answers are likely to come from utilizing
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Work from the authors’ laboratories was supported by grants from the National Institutes of Health.
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