RalGDS Functions in Ras- and cAMP-mediated Growth Stimulation

Thyroid-stimulating hormone stimulates proliferation through both the cAMP-dependent protein kinase and Ras but not through Raf-1 and mitogen-activated and extracellular signal-related kinase kinase. We now report that thyroid-stimulating hormone represses mitogen-activated protein kinase activity a...

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Bibliographic Details
Published in:The Journal of biological chemistry 1997-02, Vol.272 (9), p.5600-5605
Main Authors: Miller, Marsha J., Prigent, Sally, Kupperman, Erik, Rioux, Lise, Park, Sang-Ho, Feramisco, James R., White, Michael A., Rutkowski, J.Lynn, Meinkoth, Judy L.
Format: Article
Language:English
Subjects:
Cyclic AMP - metabolism
DNA Replication - drug effects
Genes, ras
GTP-Binding Proteins - metabolism
Insulin-Like Growth Factor I - pharmacology
Microinjections
Mitosis
Protein-Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-raf
ral Guanine Nucleotide Exchange Factor
rap GTP-Binding Proteins
Signal Transduction
Thyrotropin - pharmacology
Transcription Factors - metabolism
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Summary:Thyroid-stimulating hormone stimulates proliferation through both the cAMP-dependent protein kinase and Ras but not through Raf-1 and mitogen-activated and extracellular signal-related kinase kinase. We now report that thyroid-stimulating hormone represses mitogen-activated protein kinase activity and that microinjection of an effector domain mutant Ha-Ras protein, Ras(12V,37G), defective in Raf-1 binding and mitogen-activated protein kinase activation, stimulates DNA synthesis in quiescent and thyroid-stimulating hormone-treated thyrocytes. A yeast two-hybrid screen identified RalGDS as a Ras(12V,37G) binding protein and therefore a potential effector of Ras in these cells. Associations between Ras and RalGDS were observed in extracts prepared from thyroid cells. Microinjection of a mutant RalA(28N) protein thought to sequester RalGDS family members reduced DNA synthesis stimulated by Ras as well as cAMP-mediated DNA synthesis in two cell lines which respond to cAMP with mitogenesis. These results support the idea that RalGDS may be an effector of Ras in cAMP-mediated growth stimulation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.272.9.5600