Abstract
Simple SummaryIn this review, we provide information on the role of Vav proteins, a group of signaling molecules that act as both Rho GTPase activators and adaptor molecules, in the cardiovascular system, skeletal muscle, and the nervous system. We also describe how these functions impact in other physiological and pathological processes such as sympathoregulation, blood pressure regulation, systemic metabolism, and metabolic syndrome.Vav proteins act as tyrosine phosphorylation-regulated guanosine nucleotide exchange factors for Rho GTPases and as molecular scaffolds. In mammals, this family of signaling proteins is composed of three members (Vav1, Vav2, Vav3) that work downstream of protein tyrosine kinases in a wide variety of cellular processes. Recent work with genetically modified mouse models has revealed that these proteins play key signaling roles in vascular smooth and skeletal muscle cells, specific neuronal subtypes, and glia cells. These functions, in turn, ensure the proper regulation of blood pressure levels, skeletal muscle mass, axonal wiring, and fiber myelination events as well as systemic metabolic balance. The study of these mice has also led to the discovery of new physiological interconnection among tissues that contribute to the ontogeny and progression of different pathologies such as, for example, hypertension, cardiovascular disease, and metabolic syndrome. Here, we provide an integrated view of all these new Vav family-dependent signaling and physiological functions.
Highlights
We found that Vav2 signaling is critical for the control of skeletal muscle mass due to its implication in the regulation of the optimal output from the phosphatidylinositol 3 kinase α (PI3Kα)–Akt axis upon the stimulation of skeletal muscle cells with either insulin or IGF1 [39]
Vav2L332A/L332A and heterozygous Vav2L332A/– pharmaco-mimetic mice, we have shown that the cardiovascular defects only arise in the latter animals [38]
Many regulatory and functional issues remain to be addressed for these Vav family-dependent physiological processes in the near future
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil-. This process entails the disassembly of the F-actin cytoskeleton, of protein nitrosylation events, and of other signaling regulatory steps in NO-stimulated vascular smooth muscle cells (vSMCs) [17] To induce the former response, NO promotes the step-wise stimulation of soluble guanylate cyclase [17,19], production of cyclic guanosine monophosphate (cGMP) [17,19], and the enzyme activity of the cGMP-dependent protein kinase type I [17,19,20] (Figure 2, pathway in black color). The latter strain expresses an N-terminally truncated (residues 1 to 186) version of the protein that showed catalytic hyperactivity due to the elimination of the inhibitory CH and Ac regions (Figure 1) [36] These two mouse models allowed us to address, for the first time, the contribution of the deregulated catalytic activity of Vav to a specific biological process. These metabolic alterations are quite similar to those previously found in other genetically modified mouse models that display either reduced (as in Vav2L332A mice) or increased (as in Vav2Onc mice) skeletal muscle mass [44,45,46,47,48,49,50]
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