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JCS ePress online publication date 22 Apr 2008
doi: 10.1242/jcs.014076

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Research Article

Analysis of Fyn function in hemostasis and {alpha}IIb{beta}3-integrin signaling


Kumar B. Reddy*, Dawn M. Smith, and Edward F. Plow
* Author for correspondence (e-mail: reddyk{at}ccf.org)

Recent studies have shown that Src-family kinases (SFKs) play an important role in mediating integrin signalling, and the {beta}3 subunit of {alpha}IIb{beta}3 integrin has been shown to interact with multiple SFK members. Here, we analyzed the interactions and functional consequences of Fyn and Src binding to {alpha}IIb{beta}3. Fyn associated with the {beta}3 subunit in resting and thrombin-aggregated platelets, whereas interaction between Src and {alpha}IIb{beta}3 was seen predominantly in resting but not in thrombin-aggregated platelets. We have also observed that Fyn but not Src localized to focal adhesions in CHO cells adherent to fibrinogen through {alpha}IIb{beta}3. On the basis of these differences, we wanted to determine the sequence requirements for the interaction of Fyn and Src within the {beta}3-cytoplasmic domain. Whereas Src association required the C-terminal region of {beta}3, Fyn continued to interact with mutants that could no longer associate with Src and that contained as few as 13 membrane-proximal amino acids of the {beta}3-cytoplasmic tail. Using deletion mutants of {beta}3-cytoplasmic tails expressed as GST-fusion proteins, we narrowed down the Fyn-binding site even further to the amino acid residues 721-725 (IHDRK) of the {beta}3-cytoplasmic domain. On the basis of these observations, we explored whether Fyn-/- mice exhibited any abnormalities in hemostasis and platelet function. We found that Fyn-/- mice significantly differed in their second bleeding times compared with wild-type mice, and platelets from Fyn-/- mice exhibited delayed spreading on fibrinogen-coated surfaces. Using mutant forms of Fyn, it appears that its kinase activity is required for its localization to focal adhesions and to mediate {alpha}IIb{beta}3-dependent cell spreading. Our results suggest that Fyn and Src have distinct requirements for interaction with {alpha}IIb{beta}3; and, consequently, the two SFK can mediate different functional responses.


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