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RGS2 Inhibits Gα q ‐dependent Uveal Melanoma Cell Growth
Author(s) -
Zhang Qian,
Sjogren Benita
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02389
Subject(s) - rgs2 , cancer research , cell culture , cell growth , effector , microbiology and biotechnology , biology , signal transduction , mutant , gtpase activating protein , regulator , regulator of g protein signaling , chemistry , g protein , genetics , gene
Uveal melanoma (UM) is the most common primary intraocular cancer in adults with a high death rate as the cancer progresses. Currently, there is no targeted therapy and common treatments, like surgery and radiation therapy, can cause severe side effects. Consequently, there is a critical need to find novel therapies. The most common oncogenic mutant in uveal melanoma, Gα q Q209L ,constitutively activates downstream pathways, resulting in acceleration of abnormal cell growth. Regulator of G protein Signaling 2 (RGS2), a specific and potent negative regulator of Gα q , deactivates G q signaling through two different mechanisms, namely acting as a GTPase‐activating protein (GAP) and as an effector antagonist. Given that previous data indicate that RGS2 is unable to act as a GAP on Gα q Q209L , our central hypothesis is that RGS2 can act as an effector antagonist on this oncogenic mutant, and thereby inhibit UM cell growth. We used a UM cell line, 92.1, which expresses the Gα q Q209L mutant endogenously, as a model system. A Tet‐one inducible expression system was used to establish stable cell lines with doxycycline (dox)‐inducible RGS2 expression. We created cell lines with dox‐inducible expression of RGS2 WT , as well as two RGS2 mutants, RGS2 N149A and RGS2 S179D . RGS2 N149A does not have GAP activity towards Gα q , however, association with Gα q Q209L is maintained, as demonstrated by co‐immunoprecipitation. In contrast, RGS2 S179D associates significantly less with Gα q Q209L . Our results show that dox‐induced RGS2 expression inhibits 92.1 cell growth. RGS2 N149A has the same inhibition rate as RGS2 WT , while RGS2 S179D has no effect on cell growth. We also determined effects of RGS2 on signal pathways downstream of Gα q Q209L . Taken together our data indicates that RGS2 can inhibit uveal UM cancer cell growth by associating with Gα q Q209L . This effect is independent of the canonical GAP activity common to all RGS proteins. Instead, it indicates an effector antagonism mechanism.