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Updated: Mar 24, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Published on: June 7, 2019

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Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation

Hyeran Sung1,2, Krishna L Kanchi3, Xue Wang1,2

  • 1Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Oncotarget
|March 20, 2016
PubMed

Insights

RAS GTPase activating proteins (RasGAPs) like RASA1 are crucial in preventing tumor development. Inactivating RASA1 mutations or loss of expression in melanoma promotes tumor growth by activating R-Ras, a Ras isoform.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Ras GTPase activating proteins (RasGAPs) regulate Ras signaling, and their inactivation can promote tumor development.
  • Ras signaling pathways are frequently dysregulated in various cancers, including melanoma.

Purpose of the Study:

  • To investigate the role of RASA1 (RAS p21 protein activator 1) in melanoma development.
  • To identify novel mutations in RASA1 and assess their functional impact on melanoma cell lines.
  • To evaluate the association between RASA1 expression levels and patient survival in melanoma.

Main Methods:

  • Whole genome sequencing (WGS) of melanoma samples to identify RASA1 mutations.
  • Functional assays (soft agar colony formation, tumor growth) to assess the impact of RASA1 mutations.
  • Analysis of RASA1 expression in melanoma tissue microarrays (TMA).
  • Correlation analysis between RASA1 mRNA expression and overall survival in BRAF-mutated melanoma patients.

Main Results:

  • Two novel, clustered somatic missense mutations (Y472H and L481F) were identified in RASA1.
  • Wild-type RASA1 suppressed soft agar colony formation and tumor growth in BRAF-mutated melanoma cells, while the identified mutants did not.
  • RASA1's tumor suppressive activity was mediated through its RasGAP function towards the R-Ras isoform.
  • R-Ras activation was increased by RASA1 mutants and suppressed by wild-type RASA1, affecting Ral-A activation.
  • Loss of RASA1 expression was frequent in metastatic melanoma, and low RASA1 mRNA levels correlated with decreased overall survival in BRAF-mutated melanoma patients.

Conclusions:

  • RASA1 is inactivated in melanoma through mutation or suppressed expression.
  • RASA1 functions as a tumor suppressor in melanoma by inhibiting R-Ras.
  • Targeting RASA1 or R-Ras may offer therapeutic strategies for melanoma.
Keywords:
R-RasRASA1RasGAPmelanomawhole genome sequencing

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