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

Oncogene. 2011 Nov 10;30(45):4590-4600. doi: 10.1038/onc.2011.166. Epub 2011 May 23.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / metabolism
  • Gene Knockdown Techniques
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Male
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Mice
  • Mice, Nude
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-met / biosynthesis
  • Signal Transduction*
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Enzyme Inhibitors
  • Guanine Nucleotide Exchange Factors
  • RASGRP3 protein, human
  • Epidermal Growth Factor
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • AKT1 protein, human
  • AKT2 protein, human
  • AKT3 protein, human
  • Proto-Oncogene Proteins c-akt