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Molecular and Cellular Biology, June 2002, p. 3599-3609, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3599-3609.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

APS Facilitates c-Cbl Tyrosine Phosphorylation and GLUT4 Translocation in Response to Insulin in 3T3-L1 Adipocytes

Jun Liu, Akiko Kimura, Christian A. Baumann,,{dagger} and Alan R. Saltiel*

Department of Internal Medicine and Physiology, Life Science Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109

Received 23 October 2001/ Returned for modification 7 February 2002/ Accepted 25 February 2002

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/Y618F 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/Y618F 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/Y618F 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.

* Corresponding author. Mailing address: Life Science Institute, Department of Internal Medicine and Physiology, MSRB 1, Room 4520C, 1150 West Medical Center Dr., Ann Arbor, MI 48109-0650. Phone: (734) 615-9787. Fax: (734) 936-2888. E-mail: saltiel{at}umich.edu.

{dagger} Present address: Discovery Biology, 3-Dimensional Pharmaceuticals, Exton, Philadelphia, PA 19341.

Molecular and Cellular Biology, June 2002, p. 3599-3609, Vol. 22, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.11.3599-3609.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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