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Role for the adaptor protein Grb10 in the activation of Akt.

Grb10 is a member of the Grb7 family of adapter proteins lacking intrinsic enzymatic function and encodes functional domains including a pleckstrin homology (PH) domain and an SH2 domain. The role of different Grb10 splice variants in signal transduction of growth factors like insulin or insulin-like growth factor has been described as inhibitory or stimulatory depending on the presence of a functional PH and/or SH2 domain. Performing a yeast two-hybrid screen with the c-kit cytoplasmic tail fused to LexA as a bait and a mouse embryo cDNA library as prey, we found that the Grb10 SH2 domain interacted with the c-kit receptor tyrosine kinase. In the course of SCF-mediated activation of c-kit, Grb10 is recruited to the c-kit receptor in an SH2 domain- and phosphotyrosine-dependent but PH domain-independent manner. We found that Akt and Grb10 form a constitutive complex, suggesting a role for Grb10 in the translocation of Akt to the cell membrane. Indeed, coexpression studies revealed that Grb10 and c-kit activate Akt in a synergistic manner. This dose-dependent effect of Grb10 is wortmannin sensitive and was also seen at a lower level in cells in which c-kit was not expressed. Expression of a Grb10 mutant lacking the SH2 domain as well as a mutant lacking the PH domain did not influence Akt activity. Grb10-induced Akt activation was observed without increased phosphatidylinositol 3-kinase (PI3-kinase) activity, suggesting that Grb10 is a positive regulator of Akt downstream of PI3-kinase. Significantly, deficient activation of Akt by a constitutively activated c-kit mutant lacking the binding site for PI3-kinase (c-kitD814V/Y719F) could be fully compensated by overexpression of Grb10. In Ba/F3 cells, the incapacity of c-kitD814V/Y719F to induce interleukin-3 (IL-3)-independent growth could be rescued by overexpression of Grb10. In contrast, expression of the SH2 deletion mutant of Grb10 together with c-kitD814V/Y719F did not render Ba/F3 cells independent of IL-3. In summary, we provide evidence that Grb10 is part of the c-kit signaling pathway and that the expression level of Grb10 critically influences Akt activity. We propose a model in which Grb10 acts as a coactivator for Akt by virtue of its ability to form a complex with Akt and its SH2 domain-dependent translocation to the cell membrane.

Pubmed ID: 11809791


  • Jahn T
  • Seipel P
  • Urschel S
  • Peschel C
  • Duyster J


Molecular and cellular biology

Publication Data

February 25, 2002

Associated Grants


Mesh Terms

  • Androstadienes
  • Animals
  • Bacterial Proteins
  • Cell Fractionation
  • Cell Line
  • Chromones
  • Enzyme Activation
  • Enzyme Inhibitors
  • GRB10 Adaptor Protein
  • Humans
  • Immunoblotting
  • Morpholines
  • Phosphatidylinositol 3-Kinases
  • Precipitin Tests
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-kit
  • Recombinant Fusion Proteins
  • Serine Endopeptidases
  • Signal Transduction
  • Stem Cell Factor
  • Two-Hybrid System Techniques
  • src Homology Domains