کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2044437 1073422 2008 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Oncogenic MAPK Signaling Stimulates mTORC1 Activity by Promoting RSK-Mediated Raptor Phosphorylation
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم کشاورزی و بیولوژیک علوم کشاورزی و بیولوژیک (عمومی)
پیش نمایش صفحه اول مقاله
Oncogenic MAPK Signaling Stimulates mTORC1 Activity by Promoting RSK-Mediated Raptor Phosphorylation
چکیده انگلیسی

SummaryBackgroundThe mammalian target of rapamycin (mTOR) is a Ser/Thr kinase that controls cell growth in response to mitogens, as well as amino acid and energy sufficiency. The scaffolding protein Raptor binds to mTOR and recruits substrates to the rapamycin-sensitive mTOR complex 1 (mTORC1). Although Raptor has been shown to be essential for mTORC1 activity, the mechanisms regulating Raptor function remain unknown.ResultsHere, we demonstrate that Raptor becomes highly phosphorylated on RXRXXpS/T consensus motifs after activation of the Ras/mitogen-activated protein kinase (MAPK) pathway. Using pharmacological inhibitors and RNA interference, we show that the p90 ribosomal S6 kinases (RSKs) 1 and 2 are required for Raptor phosphorylation in vivo and directly phosphorylate Raptor in vitro. Quantitative mass spectrometry and site-directed mutagenesis revealed that RSK specifically phosphorylates Raptor within an evolutionarily conserved region with no previously known function. Interestingly, expression of oncogenic forms of Ras and MEK that elevate mTORC1 activity induced strong and constitutive phosphorylation of Raptor on these residues. Importantly, we demonstrate that expression of Raptor mutants lacking RSK-dependent phosphorylation sites markedly reduced mTOR phosphotransferase activity, indicating that RSK-mediated phosphorylation of Raptor is important for mTORC1 activation by the Ras/MAPK pathway.ConclusionsWe propose a unique mode of mTOR regulation in which RSK-mediated phosphorylation of Raptor regulates mTORC1 activity and thus suggest a means by which the Ras/MAPK pathway might promote rapamycin-sensitive signaling independently of the PI3K/Akt pathway.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: - Volume 18, Issue 17, 9 September 2008, Pages 1269–1277
نویسندگان
, , , , , , ,