Trends in Cell Biology
Integrins and Src: dynamic duo of adhesion signaling
Section snippets
Functional relationships between β3 integrins and SFKs
Integrins are expressed at the cell surface as α−β heterodimers (Figure 1a). The α and β subunits are 95–140-kDa type I transmembrane proteins, each with a relatively large extracellular domain, a single-pass transmembrane domain and a relatively short cytoplasmic domain. For example, the αIIb cytoplasmic domain contains 20 amino acid residues and the β3 cytoplasmic domain contains 47. There are two β3 integrins in vertebrates, αIIbβ3, whose expression is restricted largely to platelets and
Direct interactions between β3 integrins and SFKs
A potential explanation for these functional relationships comes from observations that c-Src can interact directly and constitutively with the β3 integrin cytoplasmic domain. Bioluminescence resonance energy transfer (BRET) and bimolecular fluorescence complementation (BiFC) techniques have been used to establish the physical proximity of αIIbβ3 and c-Src in living cells. For BRET, αIIb and c-Src were fused at their C-termini to Renilla luciferase and GFP, respectively, and coexpressed with β3
Regulation of c-Src by β3 integrins
Structural analyses of c-Src and other SFKs suggest that catalytic activity in unstimulated cells is auto-inhibited as the result of intramolecular interactions 38, 39, 40 (Figure 1b). Similar to other SH3 ligands [41], the recombinant β3 cytoplasmic domain increases c-Src catalytic activity in vitro [12]. This result can be rationalized by β3 displacement of the SH3 domain from its normal intramolecular binding site within c-Src, resulting in the release of one important restraint on c-Src
Concluding remarks
Based on the evidence summarized above, it is proposed that outside-in signaling in platelets and other cells is initiated by the ‘dynamic duo’ of β3 integrins and c-Src, whose intimate relationship is sealed by a direct interaction between the β3 cytoplasmic domain and the c-Src SH3 domain. Although this interaction is constitutive, it results in dynamic regulation of c-Src localization and activity at sites of cell adhesion. This is not to say that direct binding is the only mode by which
Acknowledgements
Work from the author's laboratory that is cited here was funded by grants from the National Institutes of Health. The author is grateful to members of his laboratory and to Joan Brugge, Mark Ginsberg and Martin Schwartz for many stimulating discussions.
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