title: Regulator of G-protein signaling 14 (RGS14) is a selective H-Ras effector.
abstract: BACKGROUND
  Regulator of G-protein signaling (RGS) proteins have been well-described as accelerators of Galpha-mediated GTP hydrolysis ("GTPase-accelerating proteins" or GAPs). However, RGS proteins with complex domain architectures are now known to regulate much more than Galpha 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.
  
  
  RESULTS
  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. Co-transfection / 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
  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.
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Willard
authors.forename: Melinda D
authors.initials: MD
authors.lastname: Willard
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Kimple
authors.forename: Meera
authors.initials: M
authors.lastname: Soundararajan
authors.forename: Emily A
authors.initials: EA
authors.lastname: Oestreich
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.forename: Nathaniel A
authors.initials: NA
authors.lastname: Sowa
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Kimple
authors.forename: Declan A
authors.initials: DA
authors.lastname: Doyle
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Zylka
authors.forename: William D
authors.initials: WD
authors.lastname: Snider
authors.forename: David P
authors.initials: DP
authors.lastname: Siderovski