Loss-of-Function Mutations in TRAF7 and KLF4 Cooperatively Activate RAS-Like GTPase Signaling and Promote Meningioma Development.
Meningiomas are the most common benign brain tumors. Mutations of the E3 ubiquitin ligase TRAF7 occur in 25% of meningiomas and commonly cooccur with mutations in KLF4, yet the functional link between TRAF7 and KLF4 mutations remains unclear. By generating an in vitro meningioma model derived from primary meningeal cells, ... we elucidated the cooperative interactions that promote meningioma development. By integrating TRAF7-driven ubiquitinome and proteome alterations in meningeal cells and the TRAF7 interactome, we identified TRAF7 as a proteostatic regulator of RAS-related small GTPases. Meningioma-associated TRAF7 mutations disrupted either its catalytic activity or its interaction with RAS GTPases. TRAF7 loss in meningeal cells altered actin dynamics and promoted anchorage-independent growth by inducing CDC42 and RAS signaling. TRAF deficiency-driven activation of the RAS/MAPK pathway promoted KLF4-dependent transcription that led to upregulation of the tumor-suppressive Semaphorin pathway, a negative regulator of small GTPases. KLF4 loss of function disrupted this negative feedback loop and enhanced mutant TRAF7-mediated cell transformation. Overall, this study provides new mechanistic insights into meningioma development, which could lead to novel treatment strategies. SIGNIFICANCE: The intricate molecular cross-talk between the ubiquitin ligase TRAF7 and the transcription factor KLF4 provides a first step toward the identification of new therapies for patients with meningioma.
Mesh Terms:
Animals, Brain Neoplasms, Cell Line, Tumor, Cell Transformation, Neoplastic, Class I Phosphatidylinositol 3-Kinases, Computational Biology, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Kruppel-Like Factor 4, Meningioma, Mice, Mice, Nude, Mutation, Neoplasm Transplantation, Proteome, Semaphorins, Sequence Analysis, DNA, Signal Transduction, Transcriptional Activation, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Ubiquitin, cdc42 GTP-Binding Protein, ras Proteins
Animals, Brain Neoplasms, Cell Line, Tumor, Cell Transformation, Neoplastic, Class I Phosphatidylinositol 3-Kinases, Computational Biology, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Kruppel-Like Factor 4, Meningioma, Mice, Mice, Nude, Mutation, Neoplasm Transplantation, Proteome, Semaphorins, Sequence Analysis, DNA, Signal Transduction, Transcriptional Activation, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Ubiquitin, cdc42 GTP-Binding Protein, ras Proteins
Cancer Res
Date: Dec. 15, 2020
PubMed ID: 34215617
View in: Pubmed Google Scholar
Download Curated Data For This Publication
234210
Switch View:
- Interactions 15