Functional Interaction of Protein Kinase Cα with the Tyrosine Kinases Syk and Src in Human Platelets

Giordano Pula, D Crosby, J Baker, A W Poole

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

Abstract

There is a high degree of cross-talk between tyrosine phosphorylation and the serine/threonine phosphorylation signaling pathways. Here we show a physical and functional interaction between the classical protein kinase C isoform (cPKC), PKCα, and two major nonreceptor tyrosine kinases in platelets, Syk and Src. In the presence of the cPKC-selective inhibitor Gö6976, platelet 5-hydroxytryptamine release was abolished in response to co-activation of glycoproteins VI and Ib-IX-V by the snake venom alboaggregin A, whereas platelet aggregation was substantially inhibited. Of the two platelet cPKCs, PKCα but not PKCβ was activated, occurring in an Syk- and phospholipase C-dependent manner. Syk and PKCα associate in a stimulation-dependent manner, requiring Syk but not PKC activity. PKCα and Syk also co-translocate from the cytosol to the plasma membrane upon platelet activation, in a manner dependent upon the activities of both kinases. Although PKCα is phosphorylated on tyrosine downstream of Syk, we provide evidence against phosphorylation of Syk by PKCα, consistent with a lack of effect of PKCα inhibition on Syk activity. PKCα also associates with Src; although in contrast to interaction with Syk, PKCα activity is required for the association of these kinases but not the stimulation-induced translocation of Src to the cell membrane. Finally, the activity of Src is negatively regulated by PKC, as shown by potentiation of Src activity in the presence of the PKC inhibitors GF109203X or Gö6976. Therefore, there is a complex interplay between PKCα, Syk, and Src involving physical interaction, phosphorylation, translocation within the cell, and functional activity regulation.
Original languageEnglish
Pages (from-to)7194-7205
Number of pages12
JournalJournal of Biological Chemistry
Volume280
Issue number8
DOIs
Publication statusPublished - 25 Feb 2005

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