Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mutations in G protein β subunits promote transformation and kinase inhibitor resistance


Activating mutations in genes encoding G protein α (Gα) subunits occur in 4–5% of all human cancers1, 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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Recurrent GNB1 and GNB2 mutations confer cytokine-independent growth.
Figure 2: Mutant Gβ proteins lose interaction with Gα subunits and induce activation of PI3K-AKT-mTOR and MAPK pathways.
Figure 3: GNB1 mutants promote myeloid dendritic cell neoplasms in vivo.
Figure 4: GNB1 and GNB2 mutations confer resistance to kinase inhibitors.

Accession codes

Primary accessions

Gene Expression Omnibus

Referenced accessions

Protein Data Bank


  1. O'Hayre, M. et al. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. Nat. Rev. Cancer 13, 412–424 (2013).

    CAS  Article  Google Scholar 

  2. Garraway, L.A. & Lander, E.S. Lessons from the cancer genome. Cell 153, 17–37 (2013).

    CAS  Article  Google Scholar 

  3. Lawrence, M.S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495–501 (2014).

    CAS  Article  Google Scholar 

  4. Iyer, G. et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 338, 221 (2012).

    CAS  Article  Google Scholar 

  5. Yoda, A. et al. Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA 107, 252–257 (2010).

    CAS  Article  Google Scholar 

  6. Shindoh, N. et al. Next-generation cDNA screening for oncogene and resistance phenotypes. PLoS ONE 7, e49201 (2012).

    CAS  Article  Google Scholar 

  7. Lucioni, M. et al. Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion. Blood 118, 4591–4594 (2011).

    CAS  Article  Google Scholar 

  8. Menezes, J. et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia 28, 823–829 (2014).

    CAS  Article  Google Scholar 

  9. Oldham, W.M. & Hamm, H.E. Heterotrimeric G protein activation by G-protein-coupled receptors. Nat. Rev. Mol. Cell Biol. 9, 60–71 (2008).

    CAS  Article  Google Scholar 

  10. Radhika, V. & Dhanasekaran, N. Transforming G proteins. Oncogene 20, 1607–1614 (2001).

    CAS  Article  Google Scholar 

  11. Van Raamsdonk, C.D. et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457, 599–602 (2009).

    CAS  Article  Google Scholar 

  12. Vallar, L., Spada, A. & Giannattasio, G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature 330, 566–568 (1987).

    CAS  Article  Google Scholar 

  13. Walter, M.J. et al. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia 27, 1275–1282 (2013).

    CAS  Article  Google Scholar 

  14. Haferlach, T. et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 28, 241–247 (2014).

    CAS  Article  Google Scholar 

  15. Ford, C.E. et al. Molecular basis for interactions of G protein βγ subunits with effectors. Science 280, 1271–1274 (1998).

    CAS  Article  Google Scholar 

  16. Wall, M.A. et al. The structure of the G protein heterotrimer Giα1β1γ2 . Cell 83, 1047–1058 (1995).

    CAS  Article  Google Scholar 

  17. Adelmant, G. et al. DNA ends alter the molecular composition and localization of Ku multicomponent complexes. Mol. Cell Proteomics 11, 411–421 (2012).

    Article  Google Scholar 

  18. Willardson, B.M. & Tracy, C.M. Chaperone-mediated assembly of G protein complexes. Subcell. Biochem. 63, 131–153 (2012).

    CAS  Article  Google Scholar 

  19. Hakak, Y. et al. The role of the GPR91 ligand succinate in hematopoiesis. J. Leukoc. Biol. 85, 837–843 (2009).

    CAS  Article  Google Scholar 

  20. Gupta, S.K. et al. Analysis of the fibroblast transformation potential of GTPase-deficient gip2 oncogenes. Mol. Cell. Biol. 12, 190–197 (1992).

    CAS  Article  Google Scholar 

  21. Stephens, L. et al. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein βγ subunits. Cell 77, 83–93 (1994).

    CAS  Article  Google Scholar 

  22. Crespo, P., Xu, N., Simonds, W.F. & Gutkind, J.S. Ras-dependent activation of MAP kinase pathway mediated by G-protein βγ subunits. Nature 369, 418–420 (1994).

    CAS  Article  Google Scholar 

  23. Camps, M. et al. Isozyme-selective stimulation of phospholipase C-β2 by G protein βγ subunits. Nature 360, 684–686 (1992).

    CAS  Article  Google Scholar 

  24. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    CAS  Article  Google Scholar 

  25. Krause, D.S., Lazarides, K., von Andrian, U.H. & Van Etten, R.A. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat. Med. 12, 1175–1180 (2006).

    CAS  Article  Google Scholar 

  26. Akagi, T. et al. Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype. Haematologica 94, 213–223 (2009).

    CAS  Article  Google Scholar 

  27. Sherborne, A.L. et al. Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nat. Genet. 42, 492–494 (2010).

    CAS  Article  Google Scholar 

  28. Tyner, J.W. et al. Kinase pathway dependence in primary human leukemias determined by rapid inhibitor screening. Cancer Res. 73, 285–296 (2013).

    CAS  Article  Google Scholar 

  29. Johannessen, C.M. et al. A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature 504, 138–142 (2013).

    CAS  Article  Google Scholar 

  30. Chapman, P.B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    CAS  Article  Google Scholar 

  31. van Bodegom, D. et al. Differences in signaling through the B-cell leukemia oncoprotein CRLF2 in response to TSLP and through mutant JAK2. Blood 120, 2853–2863 (2012).

    CAS  Article  Google Scholar 

  32. Ficarro, S.B. et al. Magnetic bead processor for rapid evaluation and optimization of parameters for phosphopeptide enrichment. Anal. Chem. 81, 4566–4575 (2009).

    CAS  Article  Google Scholar 

  33. Ficarro, S.B. et al. Online nanoflow multidimensional fractionation for high-efficiency phosphopeptide analysis. Mol. Cell Proteomics 10, O111.011064 (2011).

    Article  Google Scholar 

  34. Askenazi, M., Parikh, J.R. & Marto, J.A. mzAPI: a new strategy for efficiently sharing mass spectrometry data. Nat. Methods 6, 240–241 (2009).

    CAS  Article  Google Scholar 

  35. Parikh, J.R. et al. multiplierz: an extensible API based desktop environment for proteomics data analysis. BMC Bioinformatics 10, 364 (2009).

    Article  Google Scholar 

  36. Askenazi, M., Marto, J.A. & Linial, M. The complete peptide dictionary—a meta-proteomics resource. Proteomics 10, 4306–4310 (2010).

    CAS  Article  Google Scholar 

  37. Chapuy, B. et al. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell 24, 777–790 (2013).

    CAS  Article  Google Scholar 

  38. Weigert, O. et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J. Exp. Med. 209, 259–273 (2012).

    CAS  Article  Google Scholar 

  39. Elpek, K.G. et al. Lymphoid organ-resident dendritic cells exhibit unique transcriptional fingerprints based on subset and site. PLoS ONE 6, e23921 (2011).

    CAS  Article  Google Scholar 

Download references


We thank T. Radimerski, T. Haferlach, L. Garraway, M. Walter and N. Wagle for contributing to the manuscript. We thank A. Hawkins and the Brigham and Women's Hospital Cytogenomics Core Facility for karyotyping. This research was supported by the Aplastic Anemia and MDS International Foundation (A.Y.), the Edwards P. Evans Foundation (A.Y.), the Max-Eder Program of the Deutsche Krebshilfe (#110659 to O.W.), the Leukemia and Lymphoma Society (J.W.T.), US National Institutes of Health NCI (1R01CA183947 and 5R00CA151457 to J.W.T.), the V Foundation for Cancer Research (J.W.T.), Gabrielle's Angel Foundation for Cancer Research (J.W.T.), the Claudia Adams Barr Fund (A.Y. and D.M.W.), an American Cancer Society Research Scholar Grant (D.M.W.), a Stand Up To Cancer Innovative Research Grant (D.M.W.), and an American Society of Hematology Scholar Award (A.A.L.).

Author information

Authors and Affiliations



A.Y., G.A., J.T., B.C., N.S., Y.Y., O.W., N.K., S.-C.W., S.S.K., H.L., T.T., A.L.C., K.G.E., J.C., N.J.-S. and A.A.L. designed and performed experiments. A.Y., G.A., J.T., B.C., K.G., S.J.T., S.J.R., J.W.T., J.A.M., D.M.W. and A.A.L. analyzed data. J.G., M.W.D., H.M., J.P.M., S.J. and B.L.E. provided essential reagents. A.Y., D.M.W. and A.A.L. wrote the paper.

Corresponding authors

Correspondence to David M Weinstock or Andrew A Lane.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 78215 kb)

Supplementary Table 1

List of mutations in GNB1 and GNB2 (XLSX 16 kb)

Supplementary Table 2

Detected proteins from a band unique to the FLAG-GNB1 immuoprecipitation (XLSX 11 kb)

Supplementary Table 3

List of proteins from tandem affinity purification and mass spectrometry analysis (XLSX 28 kb)

Supplementary Table 4

List of proteins detected by phosphoproteomics analysis (XLSX 2508 kb)

Supplementary Table 5

List of phospho-sites with more than 1.5 times enrichment in TF1-GNB1 K89E cells compared to TF1 cells infected with an empty vector (XLSX 53 kb)

Supplementary Table 6

Drug screening of GNB1 K89E cells (XLSX 13 kb)

Supplementary Table 7

Assembled G protein downstream signaling pathway gene sets from MSigDB queried by GSEA in Figure 3 (XLSX 599 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yoda, A., Adelmant, G., Tamburini, J. et al. Mutations in G protein β subunits promote transformation and kinase inhibitor resistance. Nat Med 21, 71–75 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer