Inhibition of PI3K binding to activators by serine phosphorylation of PI3K regulatory subunit p85α Src homology-2 domains Academic Article uri icon


MeSH Major

  • Class Ia Phosphatidylinositol 3-Kinase
  • Enzyme Activators
  • Phosphoserine
  • src Homology Domains


  • Class IA PI3Ks are activated by growth factor receptors and generate lipid second messengers that mediate downstream responses including cell growth, cell migration, and cell survival. The p85 regulatory subunit of PI3K contains Src homology-2 (SH2) domains that mediate binding to tyrosine-phosphorylated receptors or adaptor proteins to facilitate localization and activation of PI3K at the plasma membrane. We report here that persistent activation of PKC family members by phorbol ester stimulation in cells leads to phosphorylation of two serine residues at analogous sites on both SH2 domains of p85α (S361 and S652). The modified serine residues are located in the phospho-tyrosine binding pockets of the two SH2 domains, and in the crystal structures the phosphate moieties are predicted to occupy the same space as the phosphate moieties of bound phospho-tyrosine peptides. Consistent with this prediction, phosphorylation at these serine residues or mutation to aspartate inhibits binding of p85α to tyrosine-phosphorylated peptides. We provide evidence that protein kinase D, which is phosphorylated and activated by PKCs, mediates phosphorylation of S652 in the C-terminal SH2 domain. These results reveal cross talk between PKC signaling and PI3K signaling that impairs PI3K pathway activation under conditions of persistent PKC (and protein kinase D) activity.

publication date

  • August 23, 2011



  • Academic Article



  • eng

PubMed Central ID

  • PMC3161555

Digital Object Identifier (DOI)

  • 10.1073/pnas.1107747108

PubMed ID

  • 21825134

Additional Document Info

start page

  • 14157

end page

  • 62


  • 108


  • 34