Oncogenic MAPK Signaling Stimulates mTORC1 Activity by Promoting RSK-Mediated Raptor Phosphorylation

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