Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation

Hyeran Sung, Krishna L. Kanchi, Xue Wang, Kristen S. Hill, Jane L. Messina, Ji Hyun Lee, Youngchul Kim, Nathan D. Dees, Li Ding, Jamie K. Teer, Shengyu Yang, Amod A. Sarnaik, Vernon K. Sondak, James J. Mulé, Richard K. Wilson, Jeffrey S. Weber, Minjung Kim

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Inactivation of Ras GTPase activating proteins (RasGAPs) can activate Ras, increasing the risk for tumor development. Utilizing a melanoma whole genome sequencing (WGS) data from 13 patients, we identified two novel, clustered somatic missense mutations (Y472H and L481F) in RASA1 (RAS p21 protein activator 1, also called p120RasGAP). We have shown that wild type RASA1, but not identified mutants, suppresses soft agar colony formation and tumor growth of BRAF mutated melanoma cell lines via its RasGAP activity toward R-Ras (related RAS viral (r-ras) oncogene homolog) isoform. Moreover, R-Ras increased and RASA1 suppressed Ral-A activation among Ras downstream effectors. In addition to mutations, loss of RASA1 expression was frequently observed in metastatic melanoma samples on melanoma tissue microarray (TMA) and a low level of RASA1 mRNA expression was associated with decreased overall survival in melanoma patients with BRAF mutations. Thus, these data support that RASA1 is inactivated by mutation or by suppressed expression in melanoma and that RASA1 plays a tumor suppressive role by inhibiting R-Ras, a previously less appreciated member of the Ras small GTPases.

Original languageEnglish (US)
Pages (from-to)23885-23896
Number of pages12
JournalOncotarget
Volume7
Issue number17
DOIs
StatePublished - Apr 26 2016

All Science Journal Classification (ASJC) codes

  • Oncology

Fingerprint Dive into the research topics of 'Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation'. Together they form a unique fingerprint.

Cite this