Novel Insulin Signals Regulating GLUT4 Translocation

Project: Research project

Project Details

Description

DESCRIPTION: (Scanned from the applicant's description) The overall goals of
this research proposal are to identify and characterize in the insulin signal
transduction pathways leading to the functional regulation of the protein
components directly involved in the intracellular trafficking of
GLUT4-containing vesicles. Recently, we have determined that a novel small GTP
binding protein in the Rho family (TC1O) provides essential function for the
insulin-stimulated translocation of GLUT4 in adipocytes. The functional
properties of TC1O are dependent upon several factors including appropriate
intracellular compartmentation and insulin-dependent activation into the
GTP-bound state. This is specific for TC1O as other Rho family members, RhoA,
RhoD and CDC42) are without effect. In parallel, we have also observed that CAP
plays an important role in the regulation of TC10 which apparently occurs
through its ability to recruit tyrosine phosphorylated Cbl to the lipid raft
enriched plasma membrane subdomains. In turn, the tyrosine phosphorylated Cbl
protein can engage the small adapter protein CrkIl through its SH2 domain.
Furthermore, the central SH3 domain of Crkll directly associates with C3G which
functions as a guanylnucleotide exchange factor (GEF) for TC1O. Importantly,
the assembly of this signaling cascade occurs in the lipid raft plasma membrane
subdomain due to the specific binding of CAP to the caveolar protein flotillin.
In addition, the insulin-stimulated recruitment of the CAP/Cbl complex and the
activation of TC10 through the engagement of the Crkll/C3G complex occur
independent of and parallel to the signaling pathway mediating P1 3-kinase
activation. Thus, the specific aims of this proposal are directed at defining
the mechanisms by which insulin utilizes a novel compartmentalized signal
transduction pathway that functions in concert with the P1 3-kinase pathway to
stimulate GLUT4 translocation. To accomplish these objectives we will utilize
Cbl knock-out mice to examine the role of CAP/Cbl recruitment in the activation
of TC10 and its coupling to GLUT4 translocation. We will examine the molecular
mechanism by which C3G can specifically active TC10 and then identify potential
GAPs and downstream effectors directly leading to the regulation of GLUT4
translocation. Subsequently, we will assess the role of plasma membrane lipid
raft subdomain targeting as a requirement for appropriate signal generation and
the mechanism accounting for the processing and compartmentalization of TC10.
In this manner, we hope to further developed a molecular understanding of this
novel insulin receptor dependent signaling pathway that functions in concert
with the PI 3-kinase signaling pathway to induce glucose uptake and GLUT4
translocation in adipocytes.
StatusFinished
Effective start/end date4/15/013/31/02

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $367,500.00

ASJC

  • Cell Biology

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