Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning.
Loss of tuberin, the product of TSC2 gene, increases mammalian target of rapamycin (mTOR) signaling, promoting cell growth and tumor development. However, in cells expressing tuberin, it is not known how repression of mTOR signaling is relieved to activate this pathway in response to growth factors and how hamartin participates in this process. We show that hamartin colocalizes with hypophosphorylated tuberin at the membrane, where tuberin exerts its GTPase-activating protein (GAP) activity to repress Rheb signaling. In response to growth signals, tuberin is phosphorylated by AKT and translocates to the cytosol, relieving Rheb repression. Phosphorylation of tuberin at serines 939 and 981 does not alter its intrinsic GAP activity toward Rheb but partitions tuberin to the cytosol, where it is bound by 14-3-3 proteins. Thus, tuberin bound by 14-3-3 in response to AKT phosphorylation is sequestered away from its membrane-bound activation partner (hamartin) and its target GTPase (Rheb) to relieve the growth inhibitory effects of this tumor suppressor.
Cai
Sheng-Li
SL
Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, 78957, USA.
Tee
Andrew R
AR
Short
John D
JD
Bergeron
Judith M
JM
Kim
Jinhee
J
Shen
Jianjun
J
Guo
Ruifeng
R
Johnson
Charles L
CL
Kiguchi
Kaoru
K
Walker
Cheryl Lyn
CL
D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry*; D006133:Growth Substances / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D008954:Models, Biological; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism* / Q000494:pharmacology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D006133:Growth Substances; C504241:RHEBL1 protein, human; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins