Tyrosine phosphorylation of protein kinase D in the pleckstrin homology domain leads to activation

Peter Storz, Heike Döppler, Franz Josef Johannes, Alex Toker

Research output: Contribution to journalArticlepeer-review

101 Scopus citations


Protein kinase D (PKD) is a member of the AGC family of Ser/Thr kinases and is distantly related to protein kinase C (PKC). Formerly known as PKCμ, PKD contains protein domains not found in conventional PKC isoforms. A functional pleckstrin homology (PH) domain is critical for the regulation of PKD activity. Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr432, Tyr463, and Tyr502), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr463) leads to PKD activation. By using a phospho-specific antibody, we show that Abl directly phosphorylates PKD at Tyr463 in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of PKD. Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity. These data reveal a tyrosine phosphorylation-dependent activation mechanism for PKD and suggest that this event contributes to the release of the autoinhibitory PKD PH domain leading to kinase activation and downstream responses.

Original languageEnglish (US)
Pages (from-to)17969-17976
Number of pages8
JournalJournal of Biological Chemistry
Issue number20
StatePublished - May 16 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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