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Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2008, PMID: 18056704

mTORC1 signaling can regulate growth factor activation of p44/42 mitogen-activated protein kinases through protein phosphatase 2A.

Harwood, Franklin C; Shu, Lili; Houghton, Peter J

The mTORC1 complex (mammalian target of rapamycin (mTOR)-raptor) is modulated by mitogen-activated protein (p44/42 MAP) kinases (p44/42) through phosphorylation and inactivation of the tuberous sclerosis complex. However, a role for mTORC1 signaling in modulating activation of p44/42 has not been reported. We show that in two cancer cell lines regulation of the p44/42 MAPKs is mTORC1-dependent. In Rh1 cells rapamycin inhibited insulin-like growth factor-I (IGF-I)-stimulated phosphorylation of Thr(202) but not Tyr(204) and suppressed activation of p44/42 kinase activity. Down-regulation of raptor, which inhibits mTORC1 signaling, had a similar effect to rapamycin in blocking IGF-I-stimulated Tyr(204) phosphorylation. Rapamycin did not block maximal phosphorylation of Tyr(204) but retarded the rate of dephosphorylation of Tyr(204) following IGF-I stimulation. IGF-I stimulation of MEK1 phosphorylation (Ser(217/221)) was not inhibited by rapamycin. Higher concentrations of rapamycin (> or =100 ng/ml) were required to inhibit epidermal growth factor (EGF)-induced phosphorylation of p44/42 (Thr(202)). Rapamycin-induced inhibition of p44/42 (Thr(202)) phosphorylation by IGF-I was reversed by low concentrations of okadaic acid, suggesting involvement of protein phosphatase 2A (PP2A). Both IGF-I and EGF caused dissociation of PP2A catalytic subunit (PP2Ac) from p42. Whereas low concentrations of rapamycin (1 ng/ml) inhibited dissociation of PP2Ac after IGF-I stimulation, it required higher concentrations (> or =100 ng/ml) to block EGF-induced dissociation, consistent with the ability for rapamycin to attenuate growth factor-induced activation of p44/42. The effect of rapamycin on IGF-I or insulin activation of p44/42 was recapitulated by amino acid deprivation. Rapamycin effects altering the kinetics of p44/42 phosphorylation were completely abrogated in Rh1mTORrr cells that express a rapamycin-resistant mTOR, whereas the effects of amino acid deprivation were similar in Rh1 and Rh1mTORrr cells. These results indicate complex regulation of p44/42 by phosphatases downstream of mTORC1. This suggests a model in which mTORC1 modulates the phosphorylation of Thr(202) on p44/42 MAPKs through direct or indirect regulation of PP2Ac.

Diseases/Pathways annotated by Medline MESH: MAP Kinase Signaling System
Document information provided by NCBI PubMed

Text Mining Data

p44/42 → mTORC1: " mTORC1 signaling can regulate growth factor activation of p44/42 mitogen activated protein kinases through protein phosphatase 2A "

p44/42 → mTORC1: " mTORC1 signaling can regulate growth factor activation of p44/42 mitogen activated protein kinases through protein phosphatase 2A "

p44/42 → mTORC1: " However, a role for mTORC1 signaling in modulating activation of p44/42 has not been reported "

p44/42 → mTORC1: " However, a role for mTORC1 signaling in modulating activation of p44/42 has not been reported "

Tyr → insulin-like growth factor-I (IGF-I): " In Rh1 cells rapamycin inhibited insulin-like growth factor-I (IGF-I) stimulated phosphorylation of Thr ( 202 ) but not Tyr ( 204 ) and suppressed activation of p44/42 kinase activity "

Tyr → IGF-I: " Down-regulation of raptor, which inhibits mTORC1 signaling, had a similar effect to rapamycin in blocking IGF-I stimulated Tyr ( 204 ) phosphorylation "

p44/42 → epidermal growth factor (EGF): " Higher concentrations of rapamycin ( > or =100 ng/ml ) were required to inhibit epidermal growth factor (EGF) induced phosphorylation of p44/42 ( Thr ( 202 ) ) "

p44/42 → epidermal growth factor (EGF): " Higher concentrations of rapamycin ( > or =100 ng/ml ) were required to inhibit epidermal growth factor (EGF) induced phosphorylation of p44/42 ( Thr ( 202 ) ) "

IGF-I → p44/42: " The effect of rapamycin on IGF-I or insulin activation of p44/42 was recapitulated by amino acid deprivation "

IGF-I → p44/42: " The effect of rapamycin on IGF-I or insulin activation of p44/42 was recapitulated by amino acid deprivation "

insulin → p44/42: " The effect of rapamycin on IGF-I or insulin activation of p44/42 was recapitulated by amino acid deprivation "

insulin → p44/42: " The effect of rapamycin on IGF-I or insulin activation of p44/42 was recapitulated by amino acid deprivation "

Manually curated Databases

No curated data.