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...
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| Veröffentlicht in: | The Journal of cell biology 2006-04, Vol.173 (2), p.279-289 |
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| container_title | The Journal of cell biology |
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| creator | Cai, Sheng-Li Tee, Andrew R Short, John D Bergeron, Judith M Kim, Jinhee Shen, Jianjun Guo, Ruifeng Johnson, Charles L Kiguchi, Kaoru Walker, Cheryl Lyn |
| description | 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. |
| doi_str_mv | 10.1083/jcb.200507119 |
| format | Article |
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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.</description><identifier>ISSN: 0021-9525</identifier><identifier>EISSN: 1540-8140</identifier><identifier>DOI: 10.1083/jcb.200507119</identifier><identifier>PMID: 16636147</identifier><identifier>CODEN: JCLBA3</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Antibodies ; Cell growth ; Cell Line ; Cell lines ; Cell Membrane - chemistry ; Cellular biology ; Cytosol ; Growth Substances - metabolism ; HEK293 cells ; HeLa Cells ; Humans ; Membranes ; Microscopy, Confocal ; Models, Biological ; NIH 3T3 cells ; Phosphorylation ; Physiological regulation ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Proto-Oncogene Proteins c-akt - pharmacology ; ras Proteins - metabolism ; Signal transduction ; Tuberous sclerosis ; Tumor Suppressor Proteins - analysis ; Tumor Suppressor Proteins - antagonists & inhibitors ; Tumor Suppressor Proteins - metabolism ; Tumors</subject><ispartof>The Journal of cell biology, 2006-04, Vol.173 (2), p.279-289</ispartof><rights>Copyright 2006 The Rockefeller University Press</rights><rights>Copyright Rockefeller University Press Apr 24, 2006</rights><rights>Copyright © 2006, The Rockefeller University Press 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c554t-1ac52589824c78f45295b9b140f8e5b537a2484405b8fe3c03832569fbb3f0b83</citedby><cites>FETCH-LOGICAL-c554t-1ac52589824c78f45295b9b140f8e5b537a2484405b8fe3c03832569fbb3f0b83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063818/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063818/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,886,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16636147$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cai, Sheng-Li</creatorcontrib><creatorcontrib>Tee, Andrew R</creatorcontrib><creatorcontrib>Short, John D</creatorcontrib><creatorcontrib>Bergeron, Judith M</creatorcontrib><creatorcontrib>Kim, Jinhee</creatorcontrib><creatorcontrib>Shen, Jianjun</creatorcontrib><creatorcontrib>Guo, Ruifeng</creatorcontrib><creatorcontrib>Johnson, Charles L</creatorcontrib><creatorcontrib>Kiguchi, Kaoru</creatorcontrib><creatorcontrib>Walker, Cheryl Lyn</creatorcontrib><title>Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning</title><title>The Journal of cell biology</title><addtitle>J Cell Biol</addtitle><description>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. 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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.</abstract><cop>United States</cop><pub>The Rockefeller University Press</pub><pmid>16636147</pmid><doi>10.1083/jcb.200507119</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Antibodies Cell growth Cell Line Cell lines Cell Membrane - chemistry Cellular biology Cytosol Growth Substances - metabolism HEK293 cells HeLa Cells Humans Membranes Microscopy, Confocal Models, Biological NIH 3T3 cells Phosphorylation Physiological regulation Proteins Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins c-akt - pharmacology ras Proteins - metabolism Signal transduction Tuberous sclerosis Tumor Suppressor Proteins - analysis Tumor Suppressor Proteins - antagonists & inhibitors Tumor Suppressor Proteins - metabolism Tumors |
| title | Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning |
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