Positive and Negative Regulation of TSC2 Activity and Its Effects on Downstream Effectors of the MTOR Pathway

Overview

Journal Neuromolecular Med

Specialty Biochemistry

Date 2006 Jan 5

PMID 16391386

Citations 20

Authors

Jaroslaw Jozwiak

Sergiusz Jozwiak

Tomasz Grzela

Maciej Lazarczyk

Affiliations

Soon will be listed here.

Abstract

Tuberous sclerosis is an autosomal-dominant disorder caused by the mutation of one of the two tumor suppressor genes: TSC1 or TSC2, encoding protein products, hamartin, and tuberin, respectively. Both proteins form intracellular complexes exerting inhibitory activity on mammalian target of rapamycin (mTOR) kinase. It has been demonstrated that signal transduction from tuberin to mTOR is mediated by a G protein, Ras homologue enriched in brain (Rheb). In normal cells, tuberin having GTPase-activating protein properties toward Rheb controls signals of nutrient depletion, hypoxia, or stress, not allowing activation of mTOR and subsequent protein translation and cell proliferation. However, when environmental conditions change, tuberin is phosphorylated and it forms a complex with hamartin is degraded, and downstream targets of mTOR, S6K, and eEF2K, can be activated. In this review, we summarize very recent information contributing to our knowledge of TSC2 regulation by four cellular signaling pathways: PI3K/Akt, Ras/MAPK, LKB1/AMPK, and REDD1.

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