title: SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma.
abstract: The Tel2 (also known as Telo2) and Tti1 proteins control the cellular abundance of mammalian PIKKs and are integral components of mTORC1 and mTORC2. Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. This process is primed by CK2, which translocates to the cytoplasm to mediate mTORC1-specific phosphorylation of Tel2/Tti1, subsequent to growth factor deprivation. As a consequence, mTORC1 is inactivated to restrain cell growth and protein translation whereas relief of feedback inhibition activates the PI(3)K/TORC2/Akt pathway to sustain survival. Significantly, primary human multiple myelomas exhibit high levels of Fbxo9. In this setting, PI(3)K/TORC2/Akt signalling and survival of multiple myeloma cells is dependent on Fbxo9 expression. Thus, mTORC1-specific degradation of the Tel2 and Tti1 proteins represents a central mTOR regulatory mechanism with implications in multiple myeloma, both in promoting survival and in providing targets for the specific treatment of multiple myeloma with high levels of Fbxo9 expression.
authors.affiliation: Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Fernández-Sáiz
authors.forename: Bianca-Sabrina
authors.initials: BS
authors.lastname: Targosz
authors.forename: Simone
authors.initials: S
authors.lastname: Lemeer
authors.forename: Ruth
authors.initials: R
authors.lastname: Eichner
authors.forename: Christian
authors.initials: C
authors.lastname: Langer
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Clemens
authors.initials: C
authors.lastname: Reiter
authors.forename: Julia
authors.initials: J
authors.lastname: Slotta-Huspenina
authors.forename: Sonja
authors.initials: S
authors.lastname: Schroeder
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Knorn
authors.forename: Julia
authors.initials: J
authors.lastname: Kurutz
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Michele
authors.initials: M
authors.lastname: Pagano
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kuster
authors.forename: Florian
authors.initials: F
authors.lastname: Bassermann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D047390:Casein Kinase II / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D018572:Disease-Free Survival; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D053208:Kaplan-Meier Estimate; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D046912:Multiprotein Complexes / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D010950:Plasma Cells / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism; D059748:Proteolysis; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016895:Culture Media, Serum-Free; C409823:ETV7 protein, human; D044783:F-Box Proteins; C578379:Fbxo9 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D010446:Peptide Fragments; D011506:Proteins; D050783:Proto-Oncogene Proteins c-ets; C551530:Tti1 protein, human; C546842:MTOR protein, human; D047390:Casein Kinase II; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases