PMID- 15342917 OWN - NLM STAT- MEDLINE DCOM- 20041026 LR - 20211203 IS - 0027-8424 (Print) IS - 1091-6490 (Electronic) IS - 0027-8424 (Linking) VI - 101 IP - 37 DP - 2004 Sep 14 TI - Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. PG - 13489-94 AB - Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either of the two tumor suppressor genes TSC1 or TSC2, which encode hamartin and tuberin, respectively. Tuberin and hamartin form a complex that inhibits signaling by the mammalian target of rapamycin (mTOR), a critical nutrient sensor and regulator of cell growth and proliferation. Phosphatidylinositol 3-kinase (PI3K) inactivates the tumor suppressor complex and enhances mTOR signaling by means of phosphorylation of tuberin by Akt. Importantly, cellular transformation mediated by phorbol esters and Ras isoforms that poorly activate PI3K promote tumorigenesis in the absence of Akt activation. In this study, we show that phorbol esters and activated Ras also induce the phosphorylation of tuberin and collaborates with the nutrient-sensing pathway to regulate mTOR effectors, such as p70 ribosomal S6 kinase 1 (S6K1). The mitogen-activated protein kinase (MAPK)-activated kinase, p90 ribosomal S6 kinase (RSK) 1, was found to interact with and phosphorylate tuberin at a regulatory site, Ser-1798, located at the evolutionarily conserved C terminus of tuberin. RSK1 phosphorylation of Ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mTOR signaling to S6K1. Together, our data unveil a regulatory mechanism by which the Ras/MAPK and PI3K pathways converge on the tumor suppressor tuberin to inhibit its function. FAU - Roux, Philippe P AU - Roux PP AD - Department of Cell Biology and Taplin Biological Mass Spectrometry Facility, Harvard Medical School, Boston, MA 02115, USA. FAU - Ballif, Bryan A AU - Ballif BA FAU - Anjum, Rana AU - Anjum R FAU - Gygi, Steven P AU - Gygi SP FAU - Blenis, John AU - Blenis J LA - eng GR - R01 CA046595/CA/NCI NIH HHS/United States GR - R37 CA046595/CA/NCI NIH HHS/United States GR - GM 51405/GM/NIGMS NIH HHS/United States GR - R01 GM051405/GM/NIGMS NIH HHS/United States GR - T32 HG000041/HG/NHGRI NIH HHS/United States GR - K22 HG000041/HG/NHGRI NIH HHS/United States GR - HG 00041/HG/NHGRI NIH HHS/United States GR - CA 46595/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20040901 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Repressor Proteins) RN - 0 (TSC1 protein, human) RN - 0 (TSC2 protein, human) RN - 0 (Tuberous Sclerosis Complex 1 Protein) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - 17885-08-4 (Phosphoserine) RN - 452VLY9402 (Serine) RN - 56937-68-9 (phorbolol myristate acetate) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (AKT1 protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (RPS6KA1 protein, human) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.6.5.2 (Oncogene Protein p21(ras)) RN - NI40JAQ945 (Tetradecanoylphorbol Acetate) SB - IM MH - Amino Acid Sequence MH - Animals MH - Cell Line MH - Enzyme Activation MH - Humans MH - MAP Kinase Signaling System MH - Models, Biological MH - Molecular Sequence Data MH - Mutation/genetics MH - Oncogene Protein p21(ras)/genetics/*metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphorylation MH - Phosphoserine/metabolism MH - Protein Binding MH - Protein Kinases/metabolism MH - Protein Serine-Threonine Kinases/metabolism MH - Proteins/antagonists & inhibitors/genetics/metabolism MH - Proto-Oncogene Proteins/metabolism MH - Proto-Oncogene Proteins c-akt MH - Repressor Proteins/chemistry/genetics/metabolism MH - Ribosomal Protein S6 Kinases, 90-kDa/*metabolism MH - Serine/genetics/metabolism MH - TOR Serine-Threonine Kinases MH - Tetradecanoylphorbol Acetate/*analogs & derivatives/*pharmacology MH - Tuberous Sclerosis/enzymology/genetics/*metabolism MH - Tuberous Sclerosis Complex 1 Protein MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Suppressor Proteins/*antagonists & inhibitors/metabolism PMC - PMC518784 EDAT- 2004/09/03 05:00 MHDA- 2004/10/27 09:00 PMCR- 2005/03/14 CRDT- 2004/09/03 05:00 PHST- 2004/09/03 05:00 [pubmed] PHST- 2004/10/27 09:00 [medline] PHST- 2004/09/03 05:00 [entrez] PHST- 2005/03/14 00:00 [pmc-release] AID - 0405659101 [pii] AID - 10113489 [pii] AID - 10.1073/pnas.0405659101 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13489-94. doi: 10.1073/pnas.0405659101. Epub 2004 Sep 1.