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Mol Cell Biol, February 1998, p. 872-879, Vol. 18, No. 2
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

A Novel, Multifunctional c-Cbl Binding Protein in Insulin Receptor Signaling in 3T3-L1 Adipocytes

Vered Ribon,1,2 John A. Printen,1,2 Noah G. Hoffman,3 Brian K. Kay,4 and Alan R. Saltiel1,2,*

Department of Physiology, University of Michigan School of Medicine, Ann Arbor, Michigan 481091; Department of Cell Biology, Parke-Davis Pharmaceutical Research Division, Warner Lambert Company, Ann Arbor, Michigan 481052; Department of Biology, University of North Carolina, Chapel Hill, North Carolina 275993; and Department of Pharmacology, University of Wisconsin---Madison, Madison, Wisconsin 537064

Received 9 September 1997/Returned for modification 28 October 1997/Accepted 17 November 1997

The protein product of the c-Cbl proto-oncogene is prominently tyrosine phosphorylated in response to insulin in 3T3-L1 adipocytes and not in 3T3-L1 fibroblasts. After insulin-dependent tyrosine phosphorylation, c-Cbl specifically associates with endogenous c-Crk and Fyn. These results suggest a role for tyrosine-phosphorylated c-Cbl in 3T3-L1 adipocyte activation by insulin. A yeast two-hybrid cDNA library prepared from fully differentiated 3T3-L1 adipocytes was screened with full-length c-Cbl as the target protein in an attempt to identify adipose-specific signaling proteins that interact with c-Cbl and potentially are involved in its tyrosine phosphorylation in 3T3-L1 adipocytes. Here we describe the isolation and the characterization of a novel protein that we termed CAP for c-Cbl-associated protein. CAP contains a unique structure with three adjacent Src homology 3 (SH3) domains in the C terminus and a region showing significant sequence similarity with the peptide hormone sorbin. Both CAP mRNA and proteins are expressed predominately in 3T3-L1 adipocytes and not in 3T3-L1 fibroblasts. CAP associates with c-Cbl in 3T3-L1 adipocytes independently of insulin stimulation in vivo and in vitro in an SH3-domain-mediated manner. Furthermore, we detected the association of CAP with the insulin receptor. Insulin stimulation resulted in the dissociation of CAP from the insulin receptor. Taken together, these data suggest that CAP represents a novel c-Cbl binding protein in 3T3-L1 adipocytes likely to participate in insulin signaling.

* Corresponding author. Mailing address: Parke-Davis Pharmaceutical Research Division, Warner Lambert Company, 2800 Plymouth Rd., Ann Arbor, MI 48105. Phone: (313) 996-3960. Fax: (313) 996-5668. E-mail: saltiea{at}aa.wl.com.




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