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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2004-2-9
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pubmed:abstractText |
Beyond regulating Rap activity, little is known regarding the regulation and function of the Rap GTPase-activating protein Rap1GAP. Tuberin and E6TP1 protein levels are tightly regulated through ubiquitin-mediated proteolysis. A role for these RapGAPs, along with SPA-1, as tumor suppressors has been demonstrated. Whether Rap1GAP performs a similar role was investigated. We now report that Rap1GAP protein levels are dynamically regulated in thyroid-stimulating hormone (TSH)-dependent thyroid cells. Upon TSH withdrawal, Rap1GAP undergoes a net increase in phosphorylation followed by proteasome-mediated degradation. Sequence analysis identified two putative destruction boxes in the Rap1GAP C-terminal domain. Glycogen synthase kinase 3beta (GSK3beta) phosphorylated Rap1GAP immunoprecipitated from thyroid cells, and GSK3beta inhibitors prevented phosphorylation and degradation of endogenous Rap1GAP. Co-expression of GSK3beta and Rap1GAP in human embryonic kidney 293 cells stimulated proteasome-dependent Rap1GAP turnover. Mutational analysis established a role for serine 525 in the regulation of Rap1GAP stability. Overexpression of Rap1GAP in thyroid cells impaired TSH/cAMP-stimulated p70S6 kinase activity and cell proliferation. These data are the first to show that Rap1GAP protein levels are tightly regulated and are the first to support a role for Rap1GAP as a tumor suppressor.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Bromodeoxyuridine,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/E6-target protein 1,
http://linkedlifedata.com/resource/pubmed/chemical/GTPase-Activating Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Glycogen Synthase Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Multienzyme Complexes,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Ribosomal Protein S6 Kinases, 70-kDa,
http://linkedlifedata.com/resource/pubmed/chemical/Thyrotropin,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/glycogen synthase kinase 3 beta,
http://linkedlifedata.com/resource/pubmed/chemical/rap1 GTP-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/tuberous sclerosis complex 2 protein
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
13
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pubmed:volume |
279
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5501-7
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pubmed:dateRevised |
2011-11-2
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pubmed:meshHeading |
pubmed-meshheading:14660640-Animals,
pubmed-meshheading:14660640-Blotting, Western,
pubmed-meshheading:14660640-Bromodeoxyuridine,
pubmed-meshheading:14660640-Cell Division,
pubmed-meshheading:14660640-Cell Line,
pubmed-meshheading:14660640-Cyclic AMP,
pubmed-meshheading:14660640-Cysteine Endopeptidases,
pubmed-meshheading:14660640-DNA Mutational Analysis,
pubmed-meshheading:14660640-Dose-Response Relationship, Drug,
pubmed-meshheading:14660640-GTPase-Activating Proteins,
pubmed-meshheading:14660640-Glycogen Synthase Kinase 3,
pubmed-meshheading:14660640-Humans,
pubmed-meshheading:14660640-Multienzyme Complexes,
pubmed-meshheading:14660640-Mutagenesis, Site-Directed,
pubmed-meshheading:14660640-Mutation,
pubmed-meshheading:14660640-Phosphorylation,
pubmed-meshheading:14660640-Precipitin Tests,
pubmed-meshheading:14660640-Proteasome Endopeptidase Complex,
pubmed-meshheading:14660640-Protein Structure, Tertiary,
pubmed-meshheading:14660640-Rats,
pubmed-meshheading:14660640-Rats, Wistar,
pubmed-meshheading:14660640-Repressor Proteins,
pubmed-meshheading:14660640-Ribosomal Protein S6 Kinases, 70-kDa,
pubmed-meshheading:14660640-Thyroid Gland,
pubmed-meshheading:14660640-Thyrotropin,
pubmed-meshheading:14660640-Time Factors,
pubmed-meshheading:14660640-Transfection,
pubmed-meshheading:14660640-Tumor Suppressor Proteins,
pubmed-meshheading:14660640-rap1 GTP-Binding Proteins
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pubmed:year |
2004
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pubmed:articleTitle |
Thyroid-stimulating hormone/cAMP and glycogen synthase kinase 3beta elicit opposing effects on Rap1GAP stability.
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pubmed:affiliation |
Department of Pharmacology, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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