Signal Transduction

The insulin receptor (IR) is a tyrosine kinase receptor and induces a
cellular response by phosphorylating proteins on their tyrosine
residues. The IR is known to phosphorylate several proteins in the
cytoplasm, including insulin receptor substrates (IRSs) and Shc. IRSs
and Shc function as a docking protein for SH2-domain containing
signaling molecules, which perform the next steps in the signaling
cascade. Phosphatidylinositol 3-kinase (PKI3) is one signaling molecule
that is activated by binding IRSs and is important in coupling the IR to glucose uptake. PKI3 mediates glucose uptake by the IR as well as a
variety of other cellular responses by generating PI(3,4)P2 and
PI(3,4,5)P3. PI(3,4)P2 and PI(3,4,5)P3 then function directly as second
messengers to activate downstream signaling molecules by binding
pleckstrin homology (PH) domains in these signaling molecules. To
understand the molecular mechanisms whereby PI3-kinase couples the IR to glucose uptake and other cellular responses which include cell growth,
inhibition of apoptosis, actin cytoskeletal reorganization, and protein
trafficking, we have established a novel assay in the yeast S.
cerevisiae to identify proteins that bind PI(3,4)P2 and PI(3,4,5)P3 in
vivo. Using this assay, we have identified and cloned several new PI3K
targets. Currently, we are working to elucidate the function of these
proteins in PI3K signaling.