title: RasGRP3, a Ras activator, contributes to signaling and the tumorigenic phenotype in human melanoma.
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.
authors: Laboratory of Cancer Biology and Genetics Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors: Dazhi
authors: D
authors: Yang
authors: Laboratory of Cancer Biology and Genetics Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors: Juan
authors: J
authors: Tao
authors: Laboratory of Cancer Biology and Genetics Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors: Luowei
authors: L
authors: Li
authors: Laboratory of Cancer Biology and Genetics Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors: Noemi
authors: N
authors: Kedei
authors: Neuromorphological and Neuroendocrine Research Laboratory, Department of Anatomy, Histology and Embryology, Semmelweis University and the Hungarian Academy of Sciences, Budapest, Hungary.
authors: Zsuzsanna E
authors: ZE
authors: Tóth
authors: Laboratory of Cancer Biology and Genetics Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors: Alexandra
authors: A
authors: Czap
authors: Laboratory of Cancer Biology and Genetics Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors: Julia F
authors: JF
authors: Velasquez
authors: Laboratory of Cancer Biology and Genetics Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors: Daniela
authors: D
authors: Mihova
authors: Laboratory of Cancer Biology and Genetics Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors: Aleksandra M
authors: AM
authors: Michalowski
authors: Laboratory of Cancer Biology and Genetics Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors: Stuart H
authors: SH
authors: Yuspa
authors: Laboratory of Cancer Biology and Genetics Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors: Peter M
authors: PM
authors: Blumberg
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