Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival

Cell Death Differ. 2007 Feb;14(2):368-77. doi: 10.1038/sj.cdd.4402011. Epub 2006 Jul 14.


Phosphatidylinositol 3-kinase enhancer-activating Akt (PIKE-A) binds Akt and upregulates its kinase activity, preventing apoptosis. PIKE-A can be potently phosphorylated on tyrosine residues 682 and 774, leading to its resistance to caspase cleavage. However, the upstream tyrosine kinases responsible for PIKE-A phosphorylation and subsequent physiological significance remain unknown. Here, we show that PIKE-A can be cleaved by the active apoptosome at both D474 and D592 residues. Employing fyn-deficient mouse embryonic fibroblast cells and tissues, we demonstrate that fyn is essential for phosphorylating PIKE-A and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with PIKE-A and phosphorylates it on both Y682 and Y774 residues. Tyrosine phosphorylation in PIKE-A is required for its association with active fyn but not for Akt. Mutation of D into A in PIKE-A protects it from caspase cleavage and promotes cell survival. Thus, this finding provides a molecular mechanism accounting for the antiapoptotic action of src-family tyrosine kinase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis*
  • Aspartic Acid / metabolism
  • Caspases / metabolism
  • Cell Survival
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / metabolism*
  • GTPase-Activating Proteins / chemistry
  • GTPase-Activating Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Mice
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-fyn / chemistry
  • Proto-Oncogene Proteins c-fyn / deficiency
  • Proto-Oncogene Proteins c-fyn / metabolism*
  • Substrate Specificity


  • GTPase-Activating Proteins
  • Mutant Proteins
  • Phosphotyrosine
  • Aspartic Acid
  • Proto-Oncogene Proteins c-fyn
  • Caspases
  • AGAP2 protein, human
  • GTP-Binding Proteins