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대사증후군 및 세포 신호전달 연구실
(Matabolic Syndrome and Cell Signaling Laboratory)

 

 

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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 cancer.

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  

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Matabolic Syndrome and Cell Signaling Laboratory in Institute for Cancer Research
Department of Pharmacology, College of Medicine, Chungnam National University
266 Munhwa-ro, Jung-gu, Daejeon, 35015, South Korea
Tel: +82-42-280-6768 Fax: +82-42-585-6627
COPYRIGHT ⓒ 2009 Metabolic Syndrome and Cell Signaling Laboratory, ALL RIGHTS RESERVED.