Naturally occurring hotspot cancer mutations in Gα13 promote oncogenic signaling
| Autor: | Stefano Monti, Jingyi Zhao, Anthony Federico, Xaralabos Varelas, Mikel Garcia-Marcos, Lorena Dujmusic, Zhiming Zhao, Marcin Maziarz |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Transcriptional Activation
rho GTP-Binding Proteins 0301 basic medicine Botulinum Toxins G-protein Carcinogenesis G protein Mutant GTPase Biology GTP-Binding Protein alpha Subunits G12-G13 Biochemistry Mice 03 medical and health sciences oncogene Heterotrimeric G protein Animals Humans RNA Small Interfering Molecular Biology cancer biology Adaptor Proteins Signal Transducing ADP Ribose Transferases Hippo signaling pathway 030102 biochemistry & molecular biology Oncogene Effector Molecular Bases of Disease YAP-Signaling Proteins Cell Biology Bladder Cancer GNA13 G-protein-coupled receptor (GPCR) Up-Regulation Cell biology HEK293 Cells 030104 developmental biology Urinary Bladder Neoplasms Accelerated Communications Mutagenesis Site-Directed NIH 3T3 Cells RNA Interference Acyltransferases Rho Guanine Nucleotide Exchange Factors Signal Transduction Transcription Factors |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ac120.014698 |
| Popis: | Heterotrimeric G-proteins are signaling switches broadly divided into four families based on the sequence and functional similarity of their Gα subunits: Gs, Gi/o, Gq/11, and G12/13. Artificial mutations that activate Gα subunits of each of these families have long been known to induce oncogenic transformation in experimental systems. With the advent of next-generation sequencing, activating hotspot mutations in Gs, Gi/o, or Gq/11 proteins have also been identified in patient tumor samples. In contrast, patient tumor-associated G12/13 mutations characterized to date lead to inactivation rather than activation. By using bioinformatic pathway analysis and signaling assays, here we identified cancer-associated hotspot mutations in Arg-200 of Gα13 (encoded by GNA13) as potent activators of oncogenic signaling. First, we found that components of a G12/13-dependent signaling cascade that culminates in activation of the Hippo pathway effectors YAP and TAZ is frequently altered in bladder cancer. Up-regulation of this signaling cascade correlates with increased YAP/TAZ activation transcriptional signatures in this cancer type. Among the G12/13 pathway alterations were mutations in Arg-200 of Gα13, which we validated to promote YAP/TAZ-dependent (TEAD) and MRTF-A/B-dependent (SRE.L) transcriptional activity. We further showed that this mechanism relies on the same RhoGEF-RhoGTPase cascade components that are up-regulated in bladder cancers. Moreover, Gα13 Arg-200 mutants induced oncogenic transformation in vitro as determined by focus formation assays. In summary, our findings on Gα13 mutants establish that naturally occurring hotspot mutations in Gα subunits of any of the four families of heterotrimeric G-proteins are putative cancer drivers. |
| Databáze: | OpenAIRE |
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