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Regulation of the mammalian target of rapamycin complex 2 (mTORC2)

Molle, Klaus-Dieter. Regulation of the mammalian target of rapamycin complex 2 (mTORC2). 2006, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_8473

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Abstract

The growth controlling mammalian Target of Rapamycin (mTOR) is a conserved
Ser/Thr kinase found in two structurally and functionally distinct complexes, mTORC1
and mTORC2. The tumor suppressor TSC1-TSC2 complex inhibits mTORC1 by
acting on the small GTPase Rheb, but the role of TSC1-TSC2 and Rheb in the
regulation of mTORC2 is unclear. Here we examined the role of TSC1-TSC2 in the
regulation of mTORC2 in human embryonic kidney 293 cells. Induced knockdown of
TSC1 and TSC2 (TSC1/2) stimulated mTORC2-dependent actin cytoskeleton
organization and Paxillin phosphorylation. Furthermore, TSC1/2 siRNA increased
mTORC2-dependent Ser473 phosphorylation of plasma membrane bound,
myristoylated Akt/PKB. This suggests that loss of Akt/PKB Ser473 phosphorylation
in TSC mutant cells, as reported previously, is due to inhibition of Akt/PKB
localization rather than inhibition of mTORC2 activity. Amino acids and
overexpression of Rheb failed to stimulate mTORC2 signaling. Thus, TSC1-TSC2
also inhibits mTORC2, but possibly independently of Rheb. Our results suggest that
mTORC2 hyperactivation may contribute to the pathophysiology of diseases such as
cancer and Tuberous Sclerosis Complex.
Advisors:Hall, Michael N.
Committee Members:Affolter, Markus
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N. and Affolter, Markus
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8473
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:92
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:50
Deposited On:13 Feb 2009 16:45

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