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.

Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4


Tyrosine phosphorylation is important in signaling pathways underlying tumorigenesis. We performed a mutational analysis of the protein tyrosine kinase (PTK) gene family in cutaneous metastatic melanoma. We identified 30 somatic mutations affecting the kinase domains of 19 PTKs and subsequently evaluated the entire coding regions of the genes encoding these 19 PTKs for somatic mutations in 79 melanoma samples. We found ERBB4 mutations in 19% of individuals with melanoma and found mutations in two other kinases (FLT1 and PTK2B) in 10% of individuals with melanomas. We examined seven missense mutations in the most commonly altered PTK gene, ERBB4, and found that they resulted in increased kinase activity and transformation ability. Melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA-mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib. These studies could lead to personalized therapeutics specifically targeting the kinases that are mutationally altered in individual melanomas.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Distribution of mutations in ERBB4.
Figure 2: ERBB4 mutants show increased basal activation.
Figure 3: Mutant ERBB4 induces cell transformation and anchorage-independent growth in NIH 3T3 and SK-Mel-2 cells.
Figure 4: Expression of mutant ERBB4 provides an essential cell survival signal in melanoma.
Figure 5: Melanoma lines expressing ERBB4 mutants show increased sensitivity to inhibition of ERBB by lapatinib.

Accession codes


NCBI Reference Sequence


  1. Jemal, A. et al. Cancer Statistics, 2006. CA Cancer J. Clin. 56, 106–130 (2006).

    Article  PubMed  Google Scholar 

  2. Tsao, H., Atkins, M.B. & Sober, A.J. Management of cutaneous melanoma. N. Engl. J. Med. 351, 998–1012 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Futreal, P.A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sawyers, C. Targeted cancer therapy. Nature 432, 294–297 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Sjöblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  PubMed  Google Scholar 

  6. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Godin-Heymann, N. et al. Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer Res. 67, 7319–7326 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Soung, Y.H. et al. Somatic mutations of the ERBB4 kinase domain in human cancers. Int. J. Cancer 118, 1426–1429 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bouyain, S., Longo, P.A., Li, S., Ferguson, K.M. & Leahy, D.J. The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. Proc. Natl. Acad. Sci. USA 102, 15024–15029 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Qiu, C. et al. Mechanism of activation and inhibition of the HER4/ErbB4 kinase. Structure 16, 460–467 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Riese, D.J. II, Gallo, R.M. & Settleman, J. Mutational activation of ErbB family receptor tyrosine kinases: insights into mechanisms of signal transduction and tumorigenesis. Bioessays 29, 558–565 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Frey, M.R., Edelblum, K.L., Mullane, M.T., Liang, D. & Polk, D.B. The ErbB4 growth factor receptor is required for colon epithelial cell survival in the presence of TNF. Gastroenterology 136, 217–226 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Heymach, J.V., Nilsson, M., Blumenschein, G., Papadimitrakopoulou, V. & Herbst, R. Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Clin. Cancer Res. 12, 4441s–4445s (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Grant, S., Qiao, L. & Dent, P. Roles of ERBB family receptor tyrosine kinases, and downstream signaling pathways, in the control of cell growth and survival. Front. Biosci. 7, d376–d389 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Weinstein, I.B. Addiction to oncogenes—the Achilles heal of cancer. Science 297, 63–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. McHugh, L.A. et al. Lapatinib, a dual inhibitor of ErbB-1/-2 receptors, enhances effects of combination chemotherapy in bladder cancer cells. Int. J. Oncol. 34, 1155–1163 (2009).

    CAS  PubMed  Google Scholar 

  18. Rusnak, D.W. et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol. Cancer Ther. 1, 85–94 (2001).

    CAS  PubMed  Google Scholar 

  19. Xia, W. et al. Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene 24, 6213–6221 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Shih, L.Y. et al. Heterogeneous patterns of FLT3 Asp(835) mutations in relapsed de novo acute myeloid leukemia: a comparative analysis of 120 paired diagnostic and relapse bone marrow samples. Clin. Cancer Res. 10, 1326–1332 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Pao, W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Allen, L.F., Eiseman, I.A., Fry, D.W. & Lenehan, P.F. CI-1033, an irreversible pan-erbB receptor inhibitor and its potential application for the treatment of breast cancer. Semin. Oncol. 30, 65–78 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Sharma, S.V., Bell, D.W., Settleman, J. & Haber, D.A. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer 7, 169–181 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Palavalli, L.H. et al. Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat. Genet. 41, 518–520 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gordon, D., Abajian, C. & Green, P. Consed: a graphical tool for sequence finishing. Genome Res. 8, 195–202 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Bhangale, T.R., Stephens, M. & Nickerson, D.A. Automating resequencing-based detection of insertion-deletion polymorphisms. Nat. Genet. 38, 1457–1462 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Chappell, D.B., Zaks, T.Z., Rosenberg, S.A. & Restifo, N.P. Human melanoma cells do not express Fas (Apo-1/CD95) ligand. Cancer Res. 59, 59–62 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Solomon, D.A. et al. Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma. Cancer Res. 68, 10300–10306 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Guex, N. & Peitsch, M.C. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18, 2714–2723 (1997).

    Article  CAS  PubMed  Google Scholar 

Download references


We thank B. Vogelstein, T. Waldman, D. Bell, P. Meltzer, L. Brody, G. Merlino, S. Gutkind and I. Cardenas-Navia for their helpful comments on the manuscript; members of the NISC Comparative Sequencing Program for generating the sequence data analyzed here; and S. Anderson and M. Kirby for assistance with FACS analysis. This work supported by the Intramural Research Programs of the National Human Genome Research Institute and National Cancer Institute, National Institutes of Health, USA.

Author information

Authors and Affiliations




T.D.P. and Y.S. designed the study; J.R.W. and S.A.R. collected and analyzed the melanoma samples; N.S.A., J.C.C., K.E.Y., J.C.L., the NISC Comparative Sequencing Program, P.C. and Y.S. analyzed the genetic data; T.D.P., X.W. and K.E.Y. performed and analyzed the functional data. All authors contributed to the final version of the paper.

Corresponding author

Correspondence to Yardena Samuels.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9, Supplementary Tables 1–7 and Supplementary Note (PDF 1365 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Prickett, T., Agrawal, N., Wei, X. et al. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 41, 1127–1132 (2009).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing