RGS7 is recurrently mutated in melanoma and promotes migration and invasion of human cancer cells

Nouar Qutob, Ikuo Masuho, Michal Alon, Rafi Emmanuel, Isadora Cohen, Antonella Di Pizio, Jason Madore, Abdel Elkahloun, Tamar Ziv, Ronen Levy, Jared J. Gartner, Victoria K. Hill, Jimmy C. Lin, Yael Hevroni, Polina Greenberg, Alexandra Brodezki, Steven A. Rosenberg, Mickey Kosloff, Nicholas K. Hayward, Arie AdmonMasha Y. Niv, Richard A. Scolyer, Kirill A. Martemyanov, Yardena Samuels

Research output: Contribution to journalArticlepeer-review


Analysis of 501 melanoma exomes revealed RGS7, which encodes a GTPase-accelerating protein (GAP), to be a tumor-suppressor gene. RGS7 was mutated in 11% of melanomas and was found to harbor three recurrent mutations (p.R44C, p.E383K and p.R416Q). Structural modeling of the most common recurrent mutation of the three (p.R44C) predicted that it destabilizes the protein due to the loss of an H-bond and salt bridge network between the mutated position and the serine and aspartic acid residues at positions 58 as 61, respectively. We experimentally confirmed this prediction showing that the p.R44C mutant protein is indeed destabilized. We further show RGS7 p.R44C has weaker catalytic activity for its substrate Gαo, thus providing a dual mechanism for its loss of function. Both of these effects are expected to contribute to loss of function of RGS7 resulting in increased anchorage-independent growth, migration and invasion of melanoma cells. By mutating position 56 in the R44C mutant from valine to cysteine, thereby enabling the formation of a disulfide bridge between the two mutated positions, we slightly increased the catalytic activity and reinstated protein stability, leading to the rescue of RGS7′s function as a tumor suppressor. Our findings identify RGS7 as a novel melanoma driver and point to the clinical relevance of using strategies to stabilize the protein and, thereby, restore its function.

Original languageEnglish
Article number653
Pages (from-to)1-10
JournalScientific Reports
Issue number1
StatePublished - 1 Dec 2018

Bibliographical note

Funding Information:
We thank Mr. N. K. Skamangas for technical support and Dr. A. Kovoor for the D2 receptor expression plasmid, Dr. H. Itoh for GαoA and Dr. N. Lambert for sharing the Gβγ-Venus constructs. This work was supported by NIH grants DA036596 and DA026405 (KAM). MYN is supported by Israel Science Foundation grant 432/12 and Chief Scientist Ministry of Health (the ERA-NET network) and grant no. 3–9543 from the Chief Scientist Office of the Ministry of Health, Israel via the ERA-net network. MK is supported by Israel Science Foundation grant numbers 1454/13, 1959/13, 2155/15. YS is supported by the Israel Science Foundation grant numbers 1604/13 and 877/13, the ERC (StG-335377), by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, the estate of Alice Schwarz-Gardos, the estate of John Hunter, the Knell Family, the Peter and Patricia Gruber Award and the Hamburger Family. Lady Davis Fellowship to ADP is gratefully acknowledged. NKH and RAS are supported by fellowships from the National Health and Medical Research Council of Australia.

Publisher Copyright:
© 2018 The Author(s).

ASJC Scopus subject areas

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