[HTML][HTML] Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR
K Yokogami, S Wakisaka, J Avruch, SA Reeves - Current biology, 2000 - cell.com
K Yokogami, S Wakisaka, J Avruch, SA Reeves
Current biology, 2000•cell.comNeuropoietic cytokines such as ciliary neurotrophic factor (CNTF) can activate multiple
signaling pathways in parallel, including those involving Janus kinase (JAK)–signal
transducers and activators of transcription (STATs)[1], mitogen-activated protein kinase
(MAPK)[2], phosphatidylinositol 3-kinase (PI 3-kinase) and mammalian target of rapamycin
(mTOR)–p70 S6 kinase [3]. Crosstalk occurs between these pathways, because studies
have shown that STAT3 requires phosphorylation on tyrosine and serine residues by …
signaling pathways in parallel, including those involving Janus kinase (JAK)–signal
transducers and activators of transcription (STATs)[1], mitogen-activated protein kinase
(MAPK)[2], phosphatidylinositol 3-kinase (PI 3-kinase) and mammalian target of rapamycin
(mTOR)–p70 S6 kinase [3]. Crosstalk occurs between these pathways, because studies
have shown that STAT3 requires phosphorylation on tyrosine and serine residues by …
Abstract
Neuropoietic cytokines such as ciliary neurotrophic factor (CNTF) can activate multiple signaling pathways in parallel, including those involving Janus kinase (JAK)–signal transducers and activators of transcription (STATs) [1], mitogen-activated protein kinase (MAPK) [2], phosphatidylinositol 3-kinase (PI 3-kinase) and mammalian target of rapamycin (mTOR)–p70 S6 kinase [3]. Crosstalk occurs between these pathways, because studies have shown that STAT3 requires phosphorylation on tyrosine and serine residues by independent protein kinase activities for maximal activation of target gene transcription [4]. Members of the JAK/Tyk family of tyrosine kinases mediate phosphorylation of STAT3 at Tyr705 during CNTF signaling; however, the kinase responsible for phosphorylation at STAT3 Tyr727 appears to depend on both the extracellular stimulus and the cellular context [5–8]. Here we investigate the kinase activity responsible for phosphorylation of STAT3 on Ser727 in CNTF-stimulated neuroblastoma cells. We found that CNTF-induced phosphorylation of Ser727 was inhibited by the mTOR inhibitor rapamycin, but not by inhibitors of MAPK and protein kinase C (PKC) activation. A STAT3 peptide was efficiently phosphorylated on Ser727 in a CNTF-dependent manner by mTOR, but not by a kinase-inactive mTOR mutant or by p70 S6 kinase. In agreement with these biochemical studies, rapamycin treatment of cells transfected with a STAT-responsive promoter reporter decreased activation of the reporter to the same degree as a STAT3 Ser727Ala mutant. The ability of mTOR to contribute to activation of STAT3 extends the function of mTOR [9] in mammalian cells to include transcriptional regulation.
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