ERK1/2-induced phosphorylation of R-Ras GTPases stimulates their oncogenic potential

Abstract

The Ras-related (R-Ras) isoforms TC21, R-Ras and M-Ras are members of the Ras superfamily of small GTPases. R-Ras family proteins are frequently overexpressed in human cancers, and expression of activated mutants of these GTPases is sufficient to induce cell transformation. Unlike Ras, few activating mutations of R-Ras proteins have been reported in human cancer, and very little is known about the regulation of their activity. In this study, we report that TC21 and R-Ras are phosphorylated on a conserved serine, Ser186 and Ser201, respectively, in intact cells. This residue is located in the C-terminal hypervariable region of the proteins and is not conserved in M-Ras. We show that the MAP kinases ERK1/2 phosphorylate TC21 and R-Ras on this C-terminal serine residue both in vitro and in vivo. Phosphorylation of R-Ras proteins does not affect their subcellular localization or stability but rather stimulates their activation. Phosphorylation-defective mutants of R-Ras and TC21 are compromised in their ability to promote cancer cell adhesion and migration/invasion, respectively. Importantly, we show that phosphorylation of TC21 and R-Ras potentiates their tumorigenic activity in immunodeficient mice. Our results identify a novel regulatory mechanism of the small GTPases TC21 and R-Ras that controls their oncogenic potential.

Oxysterol binding protein-like 3 (OSBPL3) is a novel driver gene that promotes tumor growth in part through R-Ras/Akt signaling in gastric cancer

“…We found 42 genes that satisfied these three criteria. Among these, we selected OSBPL3 as a candidate driver gene for further analysis because OSBPL3 has the potential to activate the R-Ras signaling pathway 6 , 7 , 22 . Notably, the OSBPL3 gene is located on chromosome 7 that was remarkably amplified in the tumor tissues of GC patients from TCGA (Fig.…”

“…OSBPL3 has been reported to activate R-Ras in HEK293 cells 6 , 7 , 22 . R-Ras promotes cell proliferation and cell cycle progression through the G1 and S phases 8 , 25 .…”

“…OSBPL3 contains an N-terminal pleckstrin homology (PH) domain and a FFAT (two phenylalanines in an acidic tract) motif. OSBPL3 binds to phosphoinositides via its PH domain 33 and binds to the ER membrane protein VAPA via its FFAT motif 22 , subsequently stimulating R-Ras signaling, as demonstrated in HEK293 cells 6 , 7 , 22 and colorectal cells 34 . In this study, we found that OSBPL3 -knockdown reduced the levels of pAkt and active R-Ras in GC cells.…”

“…It has been reported that R-Ras activates the PI3K/Akt signaling pathway similarly to Kras 13 , 14 . Interestingly, unlike Kras, few activating mutations in R-Ras have been identified in human cancers, suggesting that R-Ras is activated by other mechanisms such as phosphorylation 7 . Thus, targeting upstream genes that regulate R-Ras activity may be an attractive approach for GC treatment.…”

The Global Phosphorylation Landscape of SARS-CoV-2 Infection

“…Received: May 20, 2020 Revised: June 9, 2020 Accepted: June 23, 2020 Published: August 6, 2020 SUPPORTING CITATIONS The following references appear in the Supplemental Information: Abraham et al (2000); Alfonso et al (2011); Ali et al (2000); Amin et al (2014); Aoh et al (2009); Araujo et al (1993); Archambault and Carmena (2012); Aubrey et al (2016); Auld et al (2005); Bai et al (1996); Bakircioglu et al (2011); Bandau et al (2012); Barkley et al (2012); Bartrons et al (2018); Bassermann et al (2005); Bayliss et al (2012); Beeson (2013); Beli et al (2012); Ben Djoudi Ouadda et al (2018); Beurel et al (2015); Biaoxue et al (2016); Bieling et al (2008); Bischoff et al (1990); Bitko et al (2008); Blethrow et al (2008); Bö ck et al (2010); Boeing et al (2016); Bradshaw et al (2013); Brattsand et al (1994); Bromberg and Darnell (2000); Bruinsma et al (2014); Byon et al (1998); Cahill et al (2016a); Cahill et al (2016b); Cai et al (2006); Cai et al (2007); Casado et al (2014); Chang et al (2004); Chen et al (1999); Chen et al (2002); Chen et al (2004); Chen et al (2009); Chen et al (2013); Chen et al (2017); Cheng et al (1998); Cheng et al (2000); Chiu et al (2012); Cho et al (2019); Chou et al (1990); Chu et al (2012); Corkery et al (2015); Costa-Mattioli et al (2004); Courcelles et al (2013); Cox et al (2003); Das et al (2018); Das et al (2019); Day et al (2010); de Haan and Rottier (2005); Decker and Kovarik (2000); DeDiego et al (2011); DeDiego et al (2014); Degryse et al (2018); Deora et al (2004); Dephoure et al (2008); Díaz-Moreno et al (2009); Dou et al (2015); Eguchi et al (2009); Elia et al (2015); Ellis et al (2019);Eriksson et al (2004);Escobar et al (2015);Eto et al (2012);Eulalio et al (2007);Fallahi et al (2016);Fan et al (1997);Fan et al (2018);Fang et al (2000);Farquar et al (2008);Feldman et al (1997);Fleming et al (2000);Folker et al (2005);Foltz et al (2009);Formstecher et al (2001);Franchin et al (2015);Fré min et al (2016);Fujimoto et al (2017);Gagnon and Delpire (2010);Gao and Luo (2006);Garcia-Moreno et al (2018);Geuens et al (2017);Gherzi et al (2004);Goel et al (2015);Goldstein et al (2000);Grzenda et al (2009); Guo et al(2017);…”