RasGRP3, a Ras activator, contributes to signaling and the tumorigenic phenotype in human melanoma

D. Yang, J. Tao, L. Li, N. Kedei, Z. E. Tóth, A. Czap, J. F. Velasquez, D. Mihova, A. M. Michalowski, S. H. Yuspa, P. M. Blumberg

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27 Citations (Scopus)

Abstract

RasGRP3, an activator for H-Ras, R-Ras and Ras-associated protein-1/2, has emerged as an important mediator of signaling downstream from receptor coupled phosphoinositide turnover in B and T cells. Here, we report that RasGRP3 showed a high level of expression in multiple human melanoma cell lines as well as in a subset of human melanoma tissue samples. Suppression of endogenous RasGRP3 expression in these melanoma cell lines reduced Ras-GTP formation as well as c-Met expression and Akt phosphorylation downstream from hepatocyte growth factor (HGF) or epidermal growth factor (EGF) stimulation. RasGRP3 suppression also inhibited cell proliferation and reduced both colony formation in soft agar and xenograft tumor growth in immunodeficient mice, demonstrating the importance of RasGRP3 for the transformed phenotype of the melanoma cells. Reciprocally, overexpression of RasGRP3 in human primary melanocytes altered cellular morphology, markedly enhanced cell proliferation and rendered the cells tumorigenic in a mouse xenograft model. Suppression of RasGRP3 expression in these cells inhibited downstream RasGRP3 responses and suppressed cell growth, confirming the functional role of RasGRP3 in the altered behavior of these cells. The identification of the role of RasGRP3 in melanoma highlights its importance, as a Ras activator, in the phosphoinositide signaling pathway in human melanoma and provides a new potential therapeutic target.

Original languageEnglish
Pages (from-to)4590-4600
Number of pages11
JournalOncogene
Volume30
Issue number45
DOIs
Publication statusPublished - Nov 10 2011

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Keywords

  • Akt
  • HGF
  • Ras activator
  • cell transformation
  • guanine nucleotide exchange factor
  • melanoma

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Yang, D., Tao, J., Li, L., Kedei, N., Tóth, Z. E., Czap, A., Velasquez, J. F., Mihova, D., Michalowski, A. M., Yuspa, S. H., & Blumberg, P. M. (2011). RasGRP3, a Ras activator, contributes to signaling and the tumorigenic phenotype in human melanoma. Oncogene, 30(45), 4590-4600. https://doi.org/10.1038/onc.2011.166