| My research interests lie in the molecular mechanisms of insulin signaling. Insulin is the primary anabolic hormone in the body, and is released from the pancreas after a meal to stimulate glucose uptake into muscle, liver and fat. The relevance of insulin signaling pathways is illustrated by the fact that an absence of insulin production, or deregulation of insulin signaling in tissues such as liver, leads to the disease states termed type I and type II diabetes, respectively.
Research in my laboratory focused on a family of proteins that are key elements in the insulin-signaling pathway. Critical steps in insulin action include the initial phosphorylation of adapter proteins associated with the insulin receptor and subsequent activation of the Class Ia phosphatidylinositol 3-kinase (PI3K). One of the key components in this process is protein kinase B (PKB/Akt), which couples the activation of insulin receptors to intracellular processes controlling glucose uptake, cell growth, cell survival (anti-apoptosis), angiogenesis and gene regulation (see below).
During the past two decades a significant amount of cancer research focused on the Ras oncogene for the simple
reason that it was the first identified oncogene, and because of its prevalence
in human cancer. Over the past few years another signaling pathway downstream of
receptor tyrosine kinases has emerged, namely, the PI 3-kinase/PTEN/PKB pathway.
Several components of this pathway are deregulated in many different forms of
human cancer. Significantly the PTEN tumor suppressor gene, a phosphoinositide (PIP3) phosphatase is the second most frequently mutated gene after p53 in human
Many proto-oncogene receptor
tyrosine kinases (specific for ligands such as IGF-1, PDGF, EGF, FGF another
cytokines) signal through an autophosphorylation driven recruit-ment of
phosphoinositide 3-kinase (PI3-kinase). PI3-kinase plays a major role in the
regulation of cell growth, cell survival and cell migration through the
generation of lipid second messenger’s phosphatidylinositol-3,4-bisphosphate
(PI-3,4-P2) and phosphatidyl-inositol-3,4,5-trisphosphate (PI-3,4,5-P3) that
regulate a diverse set of signaling pathways.
A variety of proteins decode the
lipid second messenger signals by specifically binding to the lipid products of
PI3-kinase. These include the cytoplasmic tyrosine kinases of the TEC/BTK
family, Ser/Thr protein kinases of the PKB/Akt and PDK-1 families, adaptor
proteins of the IRS/GAB family and other PH domain containing proteins, such as
the exchange factors of GTP binding proteins. All these proteins bind PI-3,4-P2
and PI-3,4,5-P3 leading to membrane localization following PI3-kinase
activation. By recruiting and activating signaling complexes PI3-kinase
coordinates a complex series of signaling events. A role for PI3-kinase in human
cancer has been inferred from the fact that the tumor suppressor gene, PTEN,
a lipid phosphatase that dephosphorylate the 3 position
of the inositol ring, acts as a negativ regulaor of P3-kinas in noral
cels. In dditionconstittively @ctive frms of I3-kinae are aso oncoenic
n some pecies see tabe 1).
Theproto-ocogene KB/Akt s a
mmber ofthe secnd-messnger reulated ubfamil of proein kintses.
eceptoractivatd PI3-knase prduces P-3,4,5-3, leadng to mmbrane
attachent andsubsequnt phoshorylat@on and ctivatin of PK/Akt. Ativated
PKB/At is imlicatedin glucse metaolism, ranscritional ontrol,and in @he
reulationof apoposis inmany diferent ell typs. Furtermore,it is acentralplayer n a sigaling
pathwaytof whic many cmponent (incluing PTE, a negtive reulator f this
pathwa) have een lined to tmorigensis. PK@/Akt ha been iolated s an
ncogenefrom a ouse lyphoma, here th attachent of he vira gag seuence
alters ots sub-ellularlocatio leadin to contitutiv activaion of he
kiase. Costitutie activtion, o the ovrexpres@ion of KB/Akt een in any
hman tumrs, proably cotribute to thedevelopent of tumor y blockng
apptosis.tOur knoledge o the reeptor trosine inase ativatedPI3-kinse,
ad downsream efectors,has draaticall increa@ed overthe pas decade
Dereulationof thes signalng pathays is mplicatd in may diffeent fors
of ancer. @lthoughwe haveidentifed manyof the layers n theselipid
signalig pathwys we sill do ot havean effetive th@rapeutis that an be
utilize to tret varios cances