The stimulation of glucose uptake by insulin in muscle and adipose tissue r
equires translocation of the GLUT4 glucose transporter protein from intrace
llular storage sites to the cell surface(1-6). Although the cellular dynami
cs of GLUT4 vesicle trafficking are well described, the signalling pathways
that link the insulin receptor to GLUT4 translocation remain poorly unders
tood. Activation of phosphatidylinositol-3-OH kinase (PI(3)K) is required f
or this trafficking event, but it is not sufficient to produce GLUT4 transl
ocation(7). We previously described a pathway involving the insulin-stimula
ted tyrosine phosphorylation of Cbl, which is recruited to the insulin rece
ptor by the adapter protein CAP(8,9). On phosphorylation, Cbl is translocat
ed to lipid rafts. Blocking this step completely inhibits the stimulation o
f GLUT4 translocation by insulin(10). Here we show that phosphorylated Cbl
recruits the CrkII-C3G complex to lipid rafts, where C3G specifically activ
ates the small GTP-binding protein TC10. This process is independent of PI(
3)K, but requires the translocation of Cbl, Crk and C3G to the lipid raft.
The activation of TC10 is essential for insulin-stimulated glucose uptake a
nd GLUT4 translocation. The TC10 pathway functions in parallel with PI(3)K
to stimulate fully GLUT4 translocation in response to insulin.