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Originally published In Press as doi:10.1074/jbc.M001908200 on July 14, 2000

J. Biol. Chem., Vol. 275, Issue 40, 30901-30906, October 6, 2000
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Threonine Phosphorylation of the beta 3 Integrin Cytoplasmic Tail, at a Site Recognized by PDK1 and Akt/PKB in Vitro, Regulates Shc Binding*

Rita I. Kirk, Melissa R. Sanderson, and Kenneth M. LereaDagger

From the Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New York 10595

The mechanism of outside-in signaling by integrins parallels that for growth factor receptors. In both pathways, phosphorylation of a cytoplasmic segment on tyrosine generates a docking site for proteins containing Src homology 2 (SH2) and phosphotyrosine binding domains. We recently observed that phosphorylation of a threonine (Thr-753), six amino acids proximal to tyrosine 759 in beta 3 of the platelet specific integrin alpha IIbbeta 3, inhibits outside-in signaling through this receptor. We hypothesized that the presence of phosphothreonine 753 either renders beta 3 a poor substrate for tyrosine kinases or inhibits the docking capabilities of the tyrosyl-phosphorylated form of beta 3. The first alternative was tested by comparing the phosphorylation of beta 3 model peptides by the tyrosine kinase pp60c-src and we found that the presence of a phosphate group on a residue corresponding to Thr-753 did not detectably alter the kinetics of tyrosine phosphorylation. However, the presence of phosphate on this threonine inhibited the binding of Shc to tyrosyl-phosphorylated beta 3 peptide. The inhibitory effect of the phosphate group could be mimicked by substituting an aspartic acid for Thr-753, suggesting that a negative charge at this position modulates the binding of Shc and possibly other phosphotyrosine binding domain- and SH2-containing proteins. A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. These observations suggest that activation of PDK1 and/or Akt/PKB in platelets may modulate the binding activity and/or specificity of beta 3 for signaling molecules.

* This work was supported by Grant MCB9816832 from the National Science Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 914-594-4097; Fax: 914-594-4653; E-mail: ken_lerea@nymc.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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