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

Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

The leucine zipper-like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztrl haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztrl abrogated Ras ubiquitination at lysine-170. LZTR-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease

Using Drosophila models and tools to understand the mechanisms of novel human cancer driver gene function

The formation, overgrowth and metastasis of tumors comprise a complex series of cellular and molecular events resulting from the combined effects of a variety of aberrant signaling pathways, mutations, and epigenetic alterations. Modeling this complexity in vivo requires multiple genes to be manipulated simultaneously, which is technically challenging. Here, we analyze how Drosophila research can further contribute to identifying pathways and elucidating mechanisms underlying novel cancer driver (risk) genes associated with tumor growth and metastasis in humans.Work in the authors laboratory is supported by the Spanish Ministry of Economy and Competitiveness and co-financed by FEDER funds (BFU2015-64239-R, the Spanish State Research Agency, through the “Severo Ochoa” Program for Centers of Excellence in R&D (SEV-2013-0317), the Scientific Foundation of the Spanish Association Against Cancer (AECC) (CICPF16001DOMÍ), and the Valencian Regional Government’s Prometeo Programme for research groups of excellence (PROMETEO/2017/146) to M.D.Peer reviewe