Positive and negative regulation of TSC2 activity and its effects on downstream effectors of the mTOR pathway.
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.
Jozwiak
Jaroslaw
J
Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw, 02-004 Warsaw, ul. Chalubinskiego 5, Poland. jjozwiak@atdv.com.pl
Jozwiak
Sergiusz
S
Grzela
Tomasz
T
Lazarczyk
Maciej
M
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism* / Q000502:physiology; D018631:ras Proteins / Q000502:physiology
D000091162:AMP-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D018631:ras Proteins; C469991:DDIT4 protein, human; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C546842:MTOR protein, human; C109790:STK11 protein, human