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J. Biol. Chem., Vol. 280, Issue 1, 644-653, January 7, 2005
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Regulation of Outside-in Signaling in Platelets by Integrin-associated Protein Kinase C
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From the
Hematology-Oncology Division, Department of Medicine, University of California San Diego, La Jolla, California 92093, Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, and the ¶Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121
Studies with inhibitors have implicated protein kinase C (PKC) in the adhesive functions of integrin 
IIb
3 in platelets, but the responsible PKC isoforms and mechanisms are unknown. IIb3 interacts directly with tyrosine kinases c-Src and Syk. Therefore, we asked whether IIb3 might also interact with PKC. Of the several PKC isoforms expressed in platelets, only PKC co-immunoprecipitated with IIb3 in response to the interaction of platelets with soluble or immobilized fibrinogen. PKC recruitment to IIb3 was accompanied by a 9-fold increase in PKC activity in IIb3 immunoprecipitates. RACK1, an intracellular adapter for activated PKC, also co-immunoprecipitated with IIb3, but in this case, the interaction was constitutive. Broad spectrum PKC inhibitors blocked both PKC recruitment to IIb3 and the spread of platelets on fibrinogen. Similarly, mouse platelets that are genetically deficient in PKC spread poorly on fibrinogen, despite normal agonist-induced fibrinogen binding. In a Chinese hamster ovary cell model system, adhesion to fibrinogen caused green fluorescent protein-PKCI to associate with IIb3 and to co-localize with it at lamellipodial edges. These responses, as well as Chinese hamster ovary cell migration on fibrinogen, were blocked by the deletion of the 3 cytoplasmic tail or by co-expression of a RACK1 mutant incapable of binding to 3. These studies demonstrate that the interaction of IIb3 with activated PKC is regulated by integrin occupancy and can be mediated by RACK1 and that the interaction is required for platelet spreading triggered through IIb3. Furthermore, the studies extend the concept of IIb3 as a scaffold for multiple protein kinases that regulate the platelet actin cytoskeleton.
Received for publication, September 7, 2004 , and in revised form, November 8, 2004.
* This work was supported by National Institutes of Health Grants HL56595, HL57900, and AI38348. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| To whom correspondence should be addressed: Hematology-Oncology Div., Dept. of Medicine, University of California San Diego, Leichtag Biomedical Research Bldg., Rm. 180, 9500 Gilman Dr., Mail Code 0726, La Jolla, CA 92093. Tel.: 858-822-6425; Fax: 858-822-6444; E-mail: sshattil{at}ucsd.edu.
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