SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma
| Autor: | Anna-Maria Knorn, Bernhard Kuster, Clemens Reiter, Julia Slotta-Huspenina, Michele Pagano, Florian Bassermann, Bianca-Sabrina Targosz, Christian Peschel, Sonja Schroeder, Christian Langer, Lars Bullinger, Ruth Eichner, Vanesa Fernández-Sáiz, Julia Kurutz, Simone Lemeer |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Cell Survival medicine.medical_treatment Molecular Sequence Data Plasma Cells Gene Expression Kaplan-Meier Estimate Mechanistic Target of Rapamycin Complex 2 mTORC1 Mechanistic Target of Rapamycin Complex 1 mTORC2 Culture Media Serum-Free Disease-Free Survival Mice Cell Line Tumor medicine Animals Humans Amino Acid Sequence Phosphorylation Casein Kinase II PI3K/AKT/mTOR pathway Proto-Oncogene Proteins c-ets biology Cell growth F-Box Proteins TOR Serine-Threonine Kinases Growth factor Intracellular Signaling Peptides and Proteins Proteins Cell Biology Peptide Fragments Cell biology Ubiquitin ligase Mice Inbred C57BL Case-Control Studies Multiprotein Complexes Proteolysis biology.protein Intercellular Signaling Peptides and Proteins biological phenomena cell phenomena and immunity Signal transduction Carrier Proteins Multiple Myeloma Protein Processing Post-Translational Protein Binding Signal Transduction |
| Zdroj: | Nature Cell Biology. 15:72-81 |
| ISSN: | 1476-4679 1465-7392 |
| DOI: | 10.1038/ncb2651 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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