title: A phospho-proteomic screen identifies novel S6K1 and mTORC1 substrates revealing additional complexity in the signaling network regulating cell growth.
abstract: S6K1, a critical downstream substrate of mTORC1, has been implicated in regulating protein synthesis and a variety of processes that impinge upon cell growth and proliferation. While the role of the cytoplasmic p70(S6K1) isoform in the regulation of translation has been intensively studied, the targets and function of the nuclear p85(S6K1) isoform remain unclear. Therefore, we carried out a phospho-proteomic screen to identify novel p85(S6K1) substrates. Four novel putative p85(S6K1) substrates, GRP75, CCTβ, PGK1 and RACK1, and two mTORC1 substrates, ANXA4 and PSMA6 were identified, with diverse roles in chaperone function, ribosome maturation, metabolism, vesicle trafficking and the proteasome, respectively. The chaperonin subunit CCTβ was further investigated and the site of phosphorylation mapped to serine 260, a site located in the chaperonin apical domain. Consistent with this domain being involved in folding substrate interactions, we found that phosphorylation of serine 260 modulates chaperonin folding activity.
authors: Research Division, Peter MacCallum Cancer Centre, Melbourne, Locked Bag 1, A'Beckett Street, Victoria 8006, Australia.
authors: Katarzyna
authors: K
authors: Jastrzebski
authors: Katherine M
authors: KM
authors: Hannan
authors: Colin M
authors: CM
authors: House
authors: Sandy S-C
authors: SS
authors: Hung
authors: Richard B
authors: RB
authors: Pearson
authors: Ross D
authors: RD
authors: Hannan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017314:Annexin A4 / Q000378:metabolism; D048708:Cell Growth Processes; D002460:Cell Line; D056404:Chaperonin Containing TCP-1 / Q000737:chemistry / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000378:metabolism; D010735:Phosphoglycerate Kinase / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011506:Proteins / Q000378:metabolism* / Q000502:physiology; D040901:Proteomics; D034622:RNA Interference; D034741:RNA, Small Interfering; D000075370:Receptors for Activated C Kinase; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases
chemical_list: D017314:Annexin A4; C533298:CCT2 protein, human; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D011506:Proteins; C090294:RACK1 protein, mouse; D034741:RNA, Small Interfering; D000075370:Receptors for Activated C Kinase; C018551:glucose-regulated proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C528165:Pgk1 protein, mouse; D010735:Phosphoglycerate Kinase; C559498:PSMA6 protein, mouse; D046988:Proteasome Endopeptidase Complex; D056404:Chaperonin Containing TCP-1