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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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