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Title:Molecular Mechanism of Insulin Resistance: Role of mTOR Signaling Pathways
Author(s):Kim, Jeong-Ho
Doctoral Committee Chair(s):Belmont, Andrew S.
Department / Program:Cell and Developmental Biology
Discipline:Cell and Developmental Biology
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Biology, Molecular
Abstract:In Chapter IV, I describe another investigation of mTOR signaling mechanisms. In this study I initially set out to identify nuclear export signals in mTOR. A systematic scan of the mTOR sequence revealed 16 peptides conforming to the canonical leucine-rich nuclear export signal, of which 3 were found by reporter assays to contain LMB-sensitive and leucine-dependent nuclear export activity. Unexpectedly, mTOR proteins with those conserved leucines mutated to alanines were unable to enter the nucleus. Further investigation revealed that the L982A/L984A and L1287A/L1289A mutations likely induced a global structural change in mTOR, whereas the L545A/L547A mutation directly impaired the nuclear import of the protein---potentially regulated by a nucleocytoplasmic shuttling signal. The loss of nuclear import was accompanied by the significantly reduced ability of the L545A/L547A mutant to activate S6K1 in cells. Most importantly, when nuclear import was restored in the L545A/L547A mutant by the addition of an exogenous NLS, signaling to S6K1 was rescued. Taken together, these observations suggest the existence of a nuclear shuttling signal in mTOR, and provide definitive evidence for the requirement of mTOR nuclear import in its cytoplasmic signaling to S6K1. (Abstract shortened by UMI.).
Issue Date:2008
Type:Text
Language:English
Description:150 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2008.
URI:http://hdl.handle.net/2142/86313
Other Identifier(s):(MiAaPQ)AAI3314819
Date Available in IDEALS:2015-09-28
Date Deposited:2008


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