ArticleNature medicine2015
Mutations in G protein β subunits promote transformation and kinase inhibitor resistance.
Article in Nature medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 100 citations in OpenAlex.
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- LncRNA CCAT2 promotes the proliferation and metastasis of colorectal cancer through activation of the ERK and Wnt signaling pathways by regulating GNB2 expression.Cancer medicine · 2024Article
- Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis.Nature genetics · 2023Article
- New insights into RAS in head and neck cancer.Biochimica et biophysica acta. Reviews on cancer · 2023Review
- GNB1 promotes hepatocellular carcinoma progression by targeting BAG2 to activate P38/MAPK signaling.Cancer science · 2023Article
- An Update of G-Protein-Coupled Receptor Signaling and Its Deregulation in Gastric Carcinogenesis.Cancers · 2023Review
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29 authors at 8 institutions in 2 countries.
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Abstract
Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.
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