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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.

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Figure 1: Fbxo9 mediates degradation of the Tel2 and Tti1 proteins in response to serum withdrawal to regulate mTOR abundance and function.
Figure 2: Identification of the Fbxo9-specific phospho-degrons in Tel2 and Tti1.
Figure 3: Phospho-degron-dependent ubiquitylation of Tel2 and Tti1 via Fbxo9 regulates mTOR signalling
Figure 4: CK2 associates with Tel2 and Tti1 on growth factor withdrawal to mediate their phospho-degron-specific phosphorylation and Fbxo9-dependent degradation.
Figure 5: Fbxo9 preferentially targets mTORC1-bound Tel2/Tti1, thereby activating mTORC2 signalling.
Figure 6: Starvation increases the levels of Fbxo9 expression and Tel2/Tti1 phosphorylation, but decreases Tel2/Tti1 stability and mTORC1 activity in murine liver extracts.
Figure 7: Analyses of Fbxo9 in primary MM patient samples.
Figure 8: Fbxo9 is overexpressed in MM cells to promote survival.

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Acknowledgements

We thank T. deLange, T. Dechow, J. Duyster, D. Guardavaccaro, R. Humar, N. Mizushima and M. Rudelius for reagents; K. Engel and C. Proud for suggestions; R. Faessler and D. Moik for help with the antibody production; A. L. Illert for help with the preparation of liver extracts; and K-F. Becker for help with the reverse-phase protein arrays. M.P. is an investigator with the Howard Hughes Medical Institute. This work was supported by grants from the German Research Foundation (Emmy Noether Program, BA 2851/3-1) and the German Cancer Aid (#109543) to F.B.

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V.F-S., B-S.T. and F.B. conceived and designed the research; V.F-S. and B-S.T. performed most of the experiments with crucial help from R.E., S.S., A-M.K. and J.K.; C.L. provided the 180 MM samples, and performed cytogenetic and Fbxo9 mRNA analyses; J.S-H. provided the MM bone marrow biopsies that were processed for reverse-phase protein microarray analyses by C.R.; L.B. performed analyses of gene expression data sets; S.L. and B.K. performed mass spectrometry; M.P. provided critical reagents; V.F.S, B-S.T., R.E., S.L., C.P., M.P., B.K. and F.B. analysed results; F.B. coordinated this work and wrote the manuscript with help from V.F-S. and B-S.T. All authors discussed the results and commented on the manuscript.

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Correspondence to Vanesa Fernández-Sáiz, Bianca-Sabrina Targosz or Florian Bassermann.

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Fernández-Sáiz, V., Targosz, BS., Lemeer, S. et al. SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma. Nat Cell Biol 15, 72–81 (2013). https://doi.org/10.1038/ncb2651

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