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Belmont, Andrew S. Kim, Jeong-Ho 2015-09-28T15:03:18Z 2015-09-28T15:03:18Z 10000-01-01 2008 2008 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.). Made available in DSpace on 2015-09-28T15:03:18Z (GMT). No. of bitstreams: 2 license.txt: 4848 bytes, checksum: 96035ab3f5e1c23cc7138a224ce498bd (MD5) 3314819.pdf: 1999630 bytes, checksum: be13838593fccf6b20682a77c275706c (MD5) Previous issue date: 2008 Embargo set by: Seth Robbins for item 87594 Lift date: Forever Reason: Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs U of I Only 150 p. Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2008. http://hdl.handle.net/2142/86313 (MiAaPQ)AAI3314819 eng Biology, Molecular Molecular Mechanism of Insulin Resistance: Role of mTOR Signaling Pathways text Cell and Developmental Biology Cell and Developmental Biology University of Illinois at Urbana-Champaign Dissertation Ph.D.