The kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136

Curr Biol. 1998 Jun 18;8(13):779-82. doi: 10.1016/s0960-9822(98)70302-1.

Abstract

The c-kit-encoded receptor protein tyrosine kinase for stem cell factor (Kit/SCF-R) is essential for the development of cells within the hematopoietic, melanogenic and gametogenic lineages. SCF stimulation induces activation of phosphatidylinositol (PI) 3-kinase, which is required for SCF-induced mitogenesis and cell survival, and for activation of the serine/threonine, we found that, in response to SCF Akt became activated and mediated phosphorylation of Bad, a pro-apoptotic molecule, in a PI-3-kinase-dependent manner. Phosphorylation of Bad was restricted to Ser112 and Ser136 in vivo, but only the Akt phosphorylation sit Ser136 was essential for SCF-promoted cell survival. Furthermore, Bad and Akt interacted and colocalized in intact cells. A Kit/SCF-R gain-of-function mutant that has increased mitogenic and PI 3-kinase activation potential, due to the absence of the two protein kinase C negative feedback phosphorylation site, enhanced both Akt activation and Bad phosphorylation and also resulted in increased cell survival. Such a mechanism may account for how deregulated PI 3-kinase activity and naturally occurring gain-of-function point mutants of Kit/SCF-R lead to cellular transformation and fatal malignancies in man.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Carrier Proteins / metabolism*
  • Cell Death / physiology
  • Cell Line
  • Cell Survival / physiology
  • Enzyme Activation / physiology
  • Humans
  • Kidney / cytology
  • Oncogene Proteins / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-kit / physiology*
  • Serine / metabolism*
  • bcl-Associated Death Protein

Substances

  • BAD protein, human
  • Carrier Proteins
  • Oncogene Proteins
  • bcl-Associated Death Protein
  • Serine
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-kit
  • AKT3 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt