Disease relevance of Rala

• Ral therapy ameliorated CsA-induced osteopenia in the Ox rat and might prove a useful agent in preventing bone loss in postmenopausal women receiving CsA [1].
• The ras-related protein Ral is monoglucosylated by Clostridium sordellii lethal toxin [2].
• We investigated the role of the Ral-GDS/Ral pathway in cardiac hypertrophy [3].
• The inhibitory effects of 4 retinoids, namely, retinal (Ral), retinoic acid (RA), retinyl acetate (RAc), and retinyl palmitate (RP), and 3 carotenoid including beta-carotene (BCT), lycopene (LCP), and crocetin (CCT) on the growth and DNA synthesis of rat C-6 glioma cells were studied [4].
• Ral GDP dissociation stimulator and Ral GTPase are involved in myocardial hypertrophy [3].

High impact information on Rala

• In response to formyl-Met-Leu-Phe (fMLP) receptor stimulation, beta-arrestin Ral-GDS protein complexes dissociate and Ral-GDS translocates with beta-arrestin from the cytosol to the plasma membrane, resulting in the Ras-independent activation of the Ral effector pathway required for cytoskeletal rearrangement [5].
• beta-Arrestins are important in chemoattractant receptor-induced granule release, a process that may involve Ral-dependent regulation of the actin cytoskeleton [5].
• Ral GTPases regulate targeting of basolateral proteins in epithelial cells, secretagogue-dependent exocytosis in neuroendocrine cells and assembly of exocyst complexes [6].
• We have identified the Ral GDP dissociation stimulator (Ral-GDS) as a beta-arrestin-binding protein by yeast two-hybrid screening and co-immunoprecipitation from human polymorphonuclear neutrophilic leukocytes (PMNs) [5].
• The two Ral isoforms, RalA and -B, promote branching through distinct pathways, involving the exocyst complex and phospholipase D, respectively [7].

Chemical compound and disease context of Rala

• The aim of this study was to see whether an estrogen-like compound, Raloxifene analog (LY117018 HCL, Ral) could likewise ameliorate CsA-induced osteopenia in the Ox rat [1].

Biological context of Rala

• Here we report a novel regulatory mechanism for PLC-delta1 activation that involves direct interaction of the small GTPase Ral and the universal calcium-signaling molecule calmodulin (CaM) with PLC-delta1 [8].
• Finally, Ral-dependent branching is mediated by protein kinase C-dependent phosphorylation of 43-kD growth-associated protein, a crucial molecule involved in pathfinding, plasticity, and regeneration [7].
• In addition, depletion of endogenous Ral by RNA interference decreases branching in cortical neurons [7].
• Ral proteins are members of the Ras superfamily of small GTPases and are involved in signalling pathways for actin cytoskeleton remodelling, cell cycle control, cellular transformation and vesicle transport [9].
• RalBP1 binds specifically to the active GTP-bound form of RalA and not to a mutant Ral with a point mutation in its putative effector domain [10].

Anatomical context of Rala

• Ral GTPases regulate neurite branching through GAP-43 and the exocyst complex [7].
• Our observation also demonstrates that the spatial regulation of RalA is conducted by a mechanism distinct from the temporal regulation conducted by Ras-dependent plasma membrane recruitment of Ral guanine nucleotide exchange factors [11].
• We have examined endogenous levels of activated, GTP-bound Ral (Ral-GTP) in Rat-2 fibroblasts stimulated with various mitogens [12].
• By using fluorescence resonance energy transfer-based probes for RalA activity, we found that the EGF-induced RalA activation in Cos7 cells was restricted at the EGF-induced nascent lamellipodia, whereas under a similar condition both Ras activation and Ras-dependent translocation of Ral GEFs occurred more diffusely at the plasma membrane [11].
• They also implicate Ral GTPases and their related pathways in the assembly and function of the mitotic apparatus [13].

Associations of Rala with chemical compounds

• Ral GTPases have been implicated as mediators of Ras-induced signal transduction from observations that Ral-specific guanine nucleotide exchange factors associate with Ras and are activated by Ras [14].
• Lysophosphatidic acid (LPA) and epidermal growth factor (EGF), which activate both Ras-dependent and Ras-independent signaling pathways [10,11], rapidly activated Ral [12].
• Ral was activated by the Ca2+ ionophore ionomycin, and activation by LPA or EGF could be blocked by a phospholipase C (PLC) inhibitor [12].
• The growth stimulating effect of GS-DHN was enhanced in cells treated with antibodies directed against the glutathione conjugate transporters RLIP76 (Ral-binding protein) or the multidrug resistance protein-2 [15].
• Oophorectomy caused a significant gain in weight in groups B and C which was prevented by Ral in groups D and E. Randomized blood glucose levels and 1,25(OH)2D3 levels were elevated in both CsA-treated groups [1].

Physical interactions of Rala

• Here, we present the crystal structure of the Ral-binding domain of Exo84 in complex with active RalA [16].
• Ral also binds to phospholipase D (PLD) and thus may play a role in signaling through phospholipids [9] [12].

Regulatory relationships of Rala

• Although similar to Ras in amino acid sequence, Ral proteins are activated by a unique nucleotide exchange factor and inactivated by a distinct GTPase-activating protein [10].
• Ral-specific guanine nucleotide exchange factor such as RalGDS interacts with activated Ras and cooperates with Ras indicating that Ral can be activated through Ras signaling pathway [17].

Other interactions of Rala

• Thus, the Ral-CaM complex defines a multifaceted regulatory mechanism for PLC-delta1 activation [8].
• Cytocentrin is a Ral-binding protein involved in the assembly and function of the mitotic apparatus [13].
• Thus, the interaction of RalGDS with Ras and the subsequent activation of Ral are thought to constitute a distinct Ras-dependent signaling pathway [12].

Analytical, diagnostic and therapeutic context of Rala

• Ral (group D) completely prevented the high turnover osteopenia caused by oophorectomy and was able to attenuate substantially the effects of CsA in the Ox rat (group E) [1].
• Moreover, Ral activity was elevated in hypertrophied hearts (2.1-fold, P<0.01) by mechanical stress in association with increased CT-1 expression and signal transducer and activator of transcription 3 (STAT3) phosphorylation in the rat aortic banding model [3].

References