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 journalArticle

8 Citations (Scopus)

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

Fingerprint

Melanoma
Carcinogenesis
ras GTPase-Activating Proteins
Mutation
p120 GTPase Activating Protein
ras Proteins
Neoplasms
Monomeric GTP-Binding Proteins
ras Genes
Missense Mutation
Agar
Protein Isoforms
Genome
Cell Line
Messenger RNA
Survival
Growth
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Sung, H., Kanchi, K. L., Wang, X., Hill, K. S., Messina, J. L., Lee, J. H., ... Kim, M. (2016). Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation. Oncotarget, 7(17), 23885-23896. https://doi.org/10.18632/oncotarget.8127
Sung, Hyeran ; Kanchi, Krishna L. ; Wang, Xue ; Hill, Kristen S. ; Messina, Jane L. ; Lee, Ji Hyun ; Kim, Youngchul ; Dees, Nathan D. ; Ding, Li ; Teer, Jamie K. ; Yang, Shengyu ; Sarnaik, Amod A. ; Sondak, Vernon K. ; Mulé, James J. ; Wilson, Richard K. ; Weber, Jeffrey S. ; Kim, Minjung. / Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation. In: Oncotarget. 2016 ; Vol. 7, No. 17. pp. 23885-23896.
@article{82d62687ba314fd69ebc569245655ed6,
title = "Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation",
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.",
author = "Hyeran Sung and Kanchi, {Krishna L.} and Xue Wang and Hill, {Kristen S.} and Messina, {Jane L.} and Lee, {Ji Hyun} and Youngchul Kim and Dees, {Nathan D.} and Li Ding and Teer, {Jamie K.} and Shengyu Yang and Sarnaik, {Amod A.} and Sondak, {Vernon K.} and Mul{\'e}, {James J.} and Wilson, {Richard K.} and Weber, {Jeffrey S.} and Minjung Kim",
year = "2016",
month = "4",
day = "26",
doi = "10.18632/oncotarget.8127",
language = "English (US)",
volume = "7",
pages = "23885--23896",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "17",

}

Sung, H, Kanchi, KL, Wang, X, Hill, KS, Messina, JL, Lee, JH, Kim, Y, Dees, ND, Ding, L, Teer, JK, Yang, S, Sarnaik, AA, Sondak, VK, Mulé, JJ, Wilson, RK, Weber, JS & Kim, M 2016, 'Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation', Oncotarget, vol. 7, no. 17, pp. 23885-23896. https://doi.org/10.18632/oncotarget.8127

Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation. / Sung, Hyeran; Kanchi, Krishna L.; Wang, Xue; Hill, Kristen S.; Messina, Jane L.; Lee, Ji Hyun; Kim, Youngchul; Dees, Nathan D.; Ding, Li; Teer, Jamie K.; Yang, Shengyu; Sarnaik, Amod A.; Sondak, Vernon K.; Mulé, James J.; Wilson, Richard K.; Weber, Jeffrey S.; Kim, Minjung.

In: Oncotarget, Vol. 7, No. 17, 26.04.2016, p. 23885-23896.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation

AU - Sung, Hyeran

AU - Kanchi, Krishna L.

AU - Wang, Xue

AU - Hill, Kristen S.

AU - Messina, Jane L.

AU - Lee, Ji Hyun

AU - Kim, Youngchul

AU - Dees, Nathan D.

AU - Ding, Li

AU - Teer, Jamie K.

AU - Yang, Shengyu

AU - Sarnaik, Amod A.

AU - Sondak, Vernon K.

AU - Mulé, James J.

AU - Wilson, Richard K.

AU - Weber, Jeffrey S.

AU - Kim, Minjung

PY - 2016/4/26

Y1 - 2016/4/26

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84966586512&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84966586512&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.8127

DO - 10.18632/oncotarget.8127

M3 - Article

C2 - 26993606

AN - SCOPUS:84966586512

VL - 7

SP - 23885

EP - 23896

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 17

ER -

Sung H, Kanchi KL, Wang X, Hill KS, Messina JL, Lee JH et al. Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation. Oncotarget. 2016 Apr 26;7(17):23885-23896. https://doi.org/10.18632/oncotarget.8127