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APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes.

APS is a Cbl-binding protein that is tyrosine phosphorylated by the insulin receptor kinase. Insulin-stimulated phosphorylation of tyrosine 618 in APS is necessary for its association with c-Cbl and the subsequent tyrosine phosphorylation of Cbl by the insulin receptor in both 3T3-L1 adipocytes and CHO-IR cells. When overexpressed in these cells, wild-type APS but not an APS/Y(618)F mutant facilitated the tyrosine phosphorylation of coexpressed Cbl and its association with Crk upon insulin stimulation. APS-facilitated phosphorylation occurred on tyrosines 371, 700, and 774 in the Cbl protein. APS also interacted directly with the c-Cbl-associated protein (CAP) and colocalized with the protein in cells. The association was dependent on the SH3 domains of CAP and was independent of insulin treatment. Overexpression of the APS/Y(618)F mutant in 3T3-L1 adipocytes blocked the insulin-stimulated tyrosine phosphorylation of endogenous Cbl and binding to Crk. Moreover, the translocation of GLUT4 from intracellular vesicles to the plasma membrane was also inhibited by overexpression of the APS/Y(618)F mutant. These data suggest that APS serves as an adapter protein linking the CAP/Cbl pathway to the insulin receptor and, further, that APS-facilitated Cbl tyrosine phosphorylation catalyzed by the insulin receptor is a crucial event in the stimulation of glucose transport by insulin.

Pubmed ID: 11997497

Authors

  • Liu J
  • Kimura A
  • Baumann CA
  • Saltiel AR

Journal

Molecular and cellular biology

Publication Data

June 8, 2002

Associated Grants

None

Mesh Terms

  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing
  • Adipocytes
  • Animals
  • Biological Transport, Active
  • CHO Cells
  • Cell Differentiation
  • Cricetinae
  • Glucose
  • Glucose Transporter Type 4
  • Insulin
  • Mice
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-cbl
  • Proto-Oncogene Proteins c-crk
  • Receptor, Insulin
  • Transfection
  • Tyrosine
  • Ubiquitin-Protein Ligases