Gene interactions and pathways from curated databases and text-mining
Nat Cell Biol 2013, PMID: 23263282

SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma.

Fernández-Sáiz, Vanesa; Targosz, Bianca-Sabrina; Lemeer, Simone; Eichner, Ruth; Langer, Christian; Bullinger, Lars; Reiter, Clemens; Slotta-Huspenina, Julia; Schroeder, Sonja; Knorn, Anna-Maria; Kurutz, Julia; Peschel, Christian; Pagano, Michele; Kuster, Bernhard; Bassermann, Florian

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.

Diseases/Pathways annotated by Medline MESH: Multiple Myeloma
Document information provided by NCBI PubMed

Text Mining Data

Dashed line = No text mining data

Manually curated Databases

  • Gene Ontology Complexes SCF ubiquitin ligase complex: SCF ubiquitin ligase complex complex (FBXO2-SKP2-FBXO6-USP47-BTRC-FBXO17-TRIM21-FBXL7-FBXO15-FBXW8-CCNF-FBXO31-FBXO25-RBX1-CUL1)
  • Gene Ontology Complexes TORC2 complex: TORC2 complex complex (PINK1-RICTOR-TTI1-RPL23A)
  • Gene Ontology Complexes TORC1 complex: TORC1 complex complex (LARP1-MTOR-TTI1)
In total, 114 gene pairs are associated to this article in curated databases