PCL486H1 Lecture Notes - Lecture 6: Sirolimus, Lysosome, Cancer Cell
26 Feb 2017
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Mtor pathway integrate inputs from several intracellular and extracellular cues. Lack of o2 mtor1 activate translation and proteins. The heterodimer consisting of tuberous sclerosis 1 (tsc) and tsc2 transmits upstream signals. Impinge on mtorc1: growth factors- igf1, pi3k, mapk. Inherited mutations of tsc1/2: a lot of the signals go through to be integrated before mtor. Tsc1/2 functions as a gtpase-activating protein (gap for the ras homolog enriched in the brain (rheb) gtpase. Takes gtp and hydrolyzes inhibiting rheb-gtp rheb-gdp. Gtp-bound form of rheb directly interacts with mtorc1: strongly stimulates kinase activity. Tsc1/2 negatively regulates mtorc1 by converting rheb into its inactive gdp-bound state. Tsc1/2 are inhibitors because the remove the formation of active rheb-gtp. Tsc1/tsc2 is inhibited by akt phosphorylation on tsc2. Akt is an oncogene, when working through these pathways look far upstream. Activating akt will put and inhibitory phosphorylation more rheb-gtp activating mtorc1.
