R-Ras is required for murine dendritic cell maturation and CD4+ T-cell priming

Abstract

R-Ras is a member of the RAS superfamily of small GTP-binding proteins. The physiologic function of R-Ras has not been fully elucidated. We found that RRas is expressed by lymphoid and nonlymphoid tissues and drastically upregulated when bone marrow progenitors are induced to differentiate into dendritic cells (DCs). To address the role of R-Ras in DC functions, we generated a R-Rasdeficient mouse strain. We found that tumors induced in Rras ؊/؊ mice formed with shorter latency and attained greater tumor volumes. This finding has prompted the investigation of a role for R-Ras in the immune system. Indeed, Rras ؊/؊ mice were impaired in their ability to prime allogeneic and antigen-specific T-cell responses. Rras ؊/؊ DCs expressed lower levels of surface MHC class II and CD86 in response to lipopolysaccharide compared with wild-type DCs. This was correlated with a reduced phosphorylation of p38 and Akt. Consistently, R-Ras- IntroductionDendritic cells (DCs) are potent antigen-presenting cells with key roles in initiating antigen-specific immune responses. 1 Although numerous reports have implicated members of the RAS superfamily of GTP-binding proteins in DC biology, 2 a complete understanding of their individual roles is still lacking. Small GTPases traditionally operate as molecular switches, being inactive in the GDP-bound state and active in the GTP-bound state, therein conferring signaling function through interactions with their downstream effectors. 3 Indeed, several small GTPases have been shown to play critical roles in immune cell functions by regulating actin cytoskeleton-dependent processes. [4][5][6][7][8][9][10] Small GTPases Rap1, Rac1/2, and Cdc42, with the latter 2 being part of the RHO family of GTPases, have been demonstrated to be important in DC biology. Active Cdc42 can reactivate endocytosis in mature DCs, whereas microinjection of a dominant negative Cdc42N17 mutant abrogates the uptake of dextran. 9 Interestingly, it was demonstrated in DCs that levels of active Cdc42 and Rac were not increased in response to lipopolysaccharide (LPS). 11 However, using mature DCs from Rac1 and Rac2 double-knockout mice (Rac1/2 Ϫ/Ϫ ), Rac1 and Rac2 were shown to be critical for dendrite formation and T-cell activation. 12 In addition, RAPL, a downstream effector of Rap1, has been shown to be critical for both lymphocyte and DC migration and adhesion. 5,6 Although both Rap1 and Cdc42/Rac GTPases are clearly involved in DC biology, little is known concerning the role of other key members of the Ras subfamily.R-Ras is a small GTPase that belongs to the Ras subfamily and shares approximately 55% amino acid sequence similarity with the RAS proto-oncogenes, H-RAS, N-RAS, and K-RAS (collectively referred to as Ras herein). 13,14 Distinctively, R-Ras possesses a unique 26-amino acid sequence in the aminoterminus that is necessary for Rac activation and Rac-dependent cell spreading. 15 Furthermore, active R-Ras in macrophages has been shown to positively regulate phagocytosis of C3bi-opsonized particles via the in...

R-Ras contributes to LTP and contextual discrimination

“…In yet another study activated R-Ras activated p38 indirectly by promoting TGFb signaling (Erdogan et al, 2008). Finally, immune cells lacking R-Ras were shown to display decreased p38 activity (Singh et al, 2012). The mechanism underlying how R-Ras influences p38 in neurons is not known at present.…”

Pathological Consequence of Misguided Dendritic Cell Differentiation in Histiocytic Diseases

“…Additionally, Flt3 could be implicated in cell survival (Singh et al, 2012) and local Csf-2, which seems to exert antiapoptotic effects in nonlymphoid tissue (Greter, Helft, et al, 2012; Hirata, Egea, Dann, Eckmann, & Kagnoff, 2010). …”

OSBP-related protein 3 (ORP3) coupling with VAMP-associated protein A regulates R-Ras activity

“…In vivo studies have revealed crucial roles of R-Ras in blood vessel homeostasis, vascular regeneration, angiogenesis [36,37], and immune regulation [38]. The activity of R-Ras is controlled by semaphorin-plexin signaling which has mainly been studied in the context of neuronal axon guidance [39,40].…”