Regulator of G-protein signaling 14 (RGS14) is a selective H-Ras effector

Francis S. Willard, Melinda D. Willard, Adam J. Kimple, Meera Soundararajan, Emily A. Oestreich, Xiaoyan Li, Nathaniel A. Sowa, Randall J. Kimple, Declan A. Doyle, Channing J. Der, Mark J. Zylka, William D. Snider, David P. Siderovski

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27 Scopus citations

Abstract

Background: Regulator of G-protein signaling (RGS) proteins have been well-described as accelerators of Gα-mediated GTP hydrolysis ("GTPase-accelerating proteins" or GAPs). However, RGS proteins with complex domain architectures are now known to regulate much more than Gα GTPase activity. RGS14 contains tandem Ras-binding domains that have been reported to bind to Rap- but not Ras GTPases in vitro, leading to the suggestion that RGS14 is a Rap-specific effector. However, more recent data from mammals and Drosophila imply that, in vivo, RGS14 may instead be an effector of Ras. Methodology/Principal Findings: Full-length and truncated forms of purified RGS14 protein were found to bind indiscriminately in vitro to both Rap- and Ras-family GTPases, consistent with prior literature reports. In stark contrast, however, we found that in a cellular context RGS14 selectively binds to activated H-Ras and not to Rap isoforms. Cotransfection/co-immunoprecipitation experiments demonstrated the ability of full-length RGS14 to assemble a multiprotein complex with components of the ERK MAPK pathway in a manner dependent on activated H-Ras. Small interfering RNA-mediated knockdown of RGS14 inhibited both nerve growth factor- and basic fibrobast growth factor-mediated neuronal differentiation of PC12 cells, a process which is known to be dependent on Ras-ERK signaling. Conclusions/Significance: In cells, RGS14 facilitates the formation of a selective Ras·GTP-Raf-MEK-ERK multiprotein complex to promote sustained ERK activation and regulate H-Ras-dependent neuritogenesis. This cellular function for RGS14 is similar but distinct from that recently described for its closely-related paralogue, RGS12, which shares the tandem Ras-binding domain architecture with RGS14.

Original languageEnglish
Article numbere4884
JournalPLoS ONE
Volume4
Issue number3
DOIs
StatePublished - 25 Mar 2009

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    Willard, F. S., Willard, M. D., Kimple, A. J., Soundararajan, M., Oestreich, E. A., Li, X., Sowa, N. A., Kimple, R. J., Doyle, D. A., Der, C. J., Zylka, M. J., Snider, W. D., & Siderovski, D. P. (2009). Regulator of G-protein signaling 14 (RGS14) is a selective H-Ras effector. PLoS ONE, 4(3), [e4884]. https://doi.org/10.1371/journal.pone.0004884