Caveolin is an activator of insulin receptor signaling.
Recent data have demonstrated that caveolin, a major structural protein of caveolae, negatively regulates signaling molecules localized to caveolae. The interaction of caveolin with several caveolae-associated signaling proteins is mediated by the binding of the scaffolding region of caveolin to a hydrophobic amino acid-containing region within the regulated proteins. The presence of a similar motif within the insulin receptor kinase prompted us to investigate the caveolar localization and regulation of the insulin receptor by caveolin. We found that overexpression of caveolin-3 augmented insulin-stimulated phosphorylation of insulin receptor substrate-1 in 293T cells but not the phosphorylation of insulin receptor. Peptides corresponding to the scaffolding domain of caveolin potently stimulated insulin receptor kinase activity toward insulin receptor substrate-1 or a Src-derived peptide in vitro and in a caveolin subtype-dependent fashion. Peptides from caveolin-2 exhibited no effect, whereas caveolin-1 and -3 stimulated activity 10- and 17-fold, respectively. Peptides which increased insulin receptor kinase activity did so without affecting insulin receptor auto-phosphorylation. Furthermore, the insulin receptor bound to immobilized caveolin peptides, and this binding was inhibited in the presence of free caveolin-3 peptides. Thus, we have identified a novel mechanism by which the insulin receptor is bound and activated by specific caveolin subtypes. Furthermore, these data define a new role for caveolin as an activator of signaling.
Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212, USA.
M
M
Yamamoto
Y
Y
Toya
C
C
Schwencke
M P
MP
Lisanti
M G
MG
Myers
Y
Y
Ishikawa
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D051242:Caveolin 1; D022461:Caveolins; D002460:Cell Line; D006224:Cricetinae; D004789:Enzyme Activation; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D011972:Receptor, Insulin / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D008565:Membrane Proteins; D011994:Recombinant Proteins; D011972:Receptor, Insulin