scholarly journals The Vav GEF Family: An Evolutionary and Functional Perspective

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 465 ◽  
Author(s):  
Sonia Rodríguez-Fdez ◽  
Xosé R. Bustelo
Keyword(s):  
Tyrosine Kinases ◽  
Rho Gtpases ◽  
Nucleotide Exchange ◽  
Structural Domains ◽  
Evolutionary Transitions ◽  
Functional Perspective ◽  
Nucleotide Exchange Factors ◽  
The Family ◽  
Unicellular Organisms ◽  
Phylogenetic Perspective

Vav proteins play roles as guanosine nucleotide exchange factors for Rho GTPases and signaling adaptors downstream of protein tyrosine kinases. The recent sequencing of the genomes of many species has revealed that this protein family originated in choanozoans, a group of unicellular organisms from which animal metazoans are believed to have originated from. Since then, the Vav family underwent expansions and reductions in its members during the evolutionary transitions that originated the agnates, chondrichthyes, some teleost fish, and some neoaves. Exotic members of the family harboring atypical structural domains can be also found in some invertebrate species. In this review, we will provide a phylogenetic perspective of the evolution of the Vav family. We will also pay attention to the structure, signaling properties, regulatory layers, and functions of Vav proteins in both invertebrate and vertebrate species.

scholarly journals New Functions of Vav Family Proteins in Cardiovascular Biology, Skeletal Muscle, and the Nervous System

Biology ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 857
Author(s):  
Sonia Rodríguez-Fdez ◽  
L. Francisco Lorenzo-Martín ◽  
Salvatore Fabbiano ◽  
Mauricio Menacho-Márquez ◽  
Vincent Sauzeau ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Tyrosine Kinases ◽  
Rho Gtpases ◽  
Signaling Proteins ◽  
Nucleotide Exchange ◽  
Molecular Scaffolds ◽  
Cellular Processes ◽  
Nucleotide Exchange Factors ◽  
Cardiovascular Biology ◽  
Regulation Of Blood Pressure

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.

scholarly journals The Multiple Functions of Rho GTPases in Fission Yeasts

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1422
Author(s):  
Jero Vicente-Soler ◽  
Teresa Soto ◽  
Alejandro Franco ◽  
José Cansado ◽  
Marisa Madrid
Keyword(s):  
Fission Yeast ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Model Organism ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Physiological Processes ◽  
Evolutionary Changes ◽  
Rho Family

The Rho family of GTPases represents highly conserved molecular switches involved in a plethora of physiological processes. Fission yeast Schizosaccharomyces pombe has become a fundamental model organism to study the functions of Rho GTPases over the past few decades. In recent years, another fission yeast species, Schizosaccharomyces japonicus, has come into focus offering insight into evolutionary changes within the genus. Both fission yeasts contain only six Rho-type GTPases that are spatiotemporally controlled by multiple guanine–nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and whose intricate regulation in response to external cues is starting to be uncovered. In the present review, we will outline and discuss the current knowledge and recent advances on how the fission yeasts Rho family GTPases regulate essential physiological processes such as morphogenesis and polarity, cellular integrity, cytokinesis and cellular differentiation.

scholarly journals Hormones Secretion and Rho GTPases in Neuroendocrine Tumors

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1859
Author(s):  
Laura Streit ◽  
Laurent Brunaud ◽  
Nicolas Vitale ◽  
Stéphane Ory ◽  
Stéphane Gasman
Keyword(s):  
Neuroendocrine Tumors ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Secretory Activity ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins

Neuroendocrine tumors (NETs) belong to a heterogeneous group of neoplasms arising from hormone secreting cells. These tumors are often associated with a dysfunction of their secretory activity. Neuroendocrine secretion occurs through calcium-regulated exocytosis, a process that is tightly controlled by Rho GTPases family members. In this review, we compiled the numerous mutations and modification of expression levels of Rho GTPases or their regulators (Rho guanine nucleotide-exchange factors and Rho GTPase-activating proteins) that have been identified in NETs. We discussed how they might regulate neuroendocrine secretion.

scholarly journals p190RhoGAPs, the ARHGAP35- and ARHGAP5-Encoded Proteins, in Health and Disease

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 351 ◽  
Author(s):  
Héraud ◽  
Pinault ◽  
Lagrée ◽  
Moreau
Keyword(s):  
Rho Gtpases ◽  
Large Family ◽  
Negative Regulator ◽  
Nucleotide Exchange ◽  
Cellular Mechanisms ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Physiological Processes ◽  
Ras Superfamily ◽  
Spatio Temporal

Small guanosine triphosphatases (GTPases) gathered in the Rat sarcoma (Ras) superfamily represent a large family of proteins involved in several key cellular mechanisms. Within the Ras superfamily, the Ras homolog (Rho) family is specialized in the regulation of actin cytoskeleton-based mechanisms. These proteins switch between an active and an inactive state, resulting in subsequent inhibiting or activating downstream signals, leading finally to regulation of actin-based processes. The On/Off status of Rho GTPases implicates two subsets of regulators: GEFs (guanine nucleotide exchange factors), which favor the active GTP (guanosine triphosphate) status of the GTPase and GAPs (GTPase activating proteins), which inhibit the GTPase by enhancing the GTP hydrolysis. In humans, the 20 identified Rho GTPases are regulated by over 70 GAP proteins suggesting a complex, but well-defined, spatio-temporal implication of these GAPs. Among the quite large number of RhoGAPs, we focus on p190RhoGAP, which is known as the main negative regulator of RhoA, but not exclusively. Two isoforms, p190A and p190B, are encoded by ARHGAP35 and ARHGAP5 genes, respectively. We describe here the function of each of these isoforms in physiological processes and sum up findings on their role in pathological conditions such as neurological disorders and cancers.

scholarly journals The Phosphatidylinositol (3,4,5)-Trisphosphate-dependent Rac Exchanger 1·Ras-related C3 Botulinum Toxin Substrate 1 (P-Rex1·Rac1) Complex Reveals the Basis of Rac1 Activation in Breast Cancer Cells

2015 ◽  
Vol 290 (34) ◽  
pp. 20827-20840 ◽  
Author(s):  
Christina M. Lucato ◽  
Michelle L. Halls ◽  
Lisa M. Ooms ◽  
Heng-Jia Liu ◽  
Christina A. Mitchell ◽  
...  
Keyword(s):  
Botulinum Toxin ◽  
Tyrosine Kinases ◽  
Critical Role ◽  
Structural Data ◽  
Guanine Nucleotide Exchange Factors ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Rac Gtpases ◽  
G Protein Coupled

The P-Rex (phosphatidylinositol (3,4,5)-trisphosphate (PIP3)-dependent Rac exchanger) family (P-Rex1 and P-Rex2) of the Rho guanine nucleotide exchange factors (Rho GEFs) activate Rac GTPases to regulate cell migration, invasion, and metastasis in several human cancers. The family is unique among Rho GEFs, as their activity is regulated by the synergistic binding of PIP3 and Gβγ at the plasma membrane. However, the molecular mechanism of this family of multi-domain proteins remains unclear. We report the 1.95 Å crystal structure of the catalytic P-Rex1 DH-PH tandem domain in complex with its cognate GTPase, Rac1 (Ras-related C3 botulinum toxin substrate-1). Mutations in the P-Rex1·Rac1 interface revealed a critical role for this complex in signaling downstream of receptor tyrosine kinases and G protein-coupled receptors. The structural data indicated that the PIP3/Gβγ binding sites are on the opposite surface and markedly removed from the Rac1 interface, supporting a model whereby P-Rex1 binding to PIP3 and/or Gβγ releases inhibitory C-terminal domains to expose the Rac1 binding site.

scholarly journals Requirements for Vav Guanine Nucleotide Exchange Factors and Rho GTPases in FcγR- and Complement-Mediated Phagocytosis

Immunity ◽  
2006 ◽  
Vol 24 (3) ◽  
pp. 305-316 ◽  
Author(s):  
Amy B. Hall ◽  
M. Angelica Martinez Gakidis ◽  
Michael Glogauer ◽  
Julie L. Wilsbacher ◽  
Sizhen Gao ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

Detection of Rho GEF and GAP activity through a sensitive split luciferase assay system

2012 ◽  
Vol 441 (3) ◽  
pp. 869-880 ◽  
Author(s):  
Erik L. Anderson ◽  
Michael J. Hamann
Keyword(s):  
Rho Gtpases ◽  
Regulatory Protein ◽  
Effector Proteins ◽  
Luciferase Assay ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
P21 Activated Kinase ◽  
Rho Gef ◽  
Split Luciferase

Rho GTPases regulate the assembly of cellular actin structures and are activated by GEFs (guanine-nucleotide-exchange factors) and rendered inactive by GAPs (GTPase-activating proteins). Using the Rho GTPases Cdc42, Rac1 and RhoA, and the GTPase-binding portions of the effector proteins p21-activated kinase and Rhophilin1, we have developed split luciferase assays for detecting both GEF and GAP regulation of these GTPases. The system relies on purifying split luciferase fusion proteins of the GTPases and effectors from bacteria, and our results show that the assays replicate GEF and GAP specificities at nanomolar concentrations for several previously characterized Rho family GEFs (Dbl, Vav2, Trio and Asef) and GAPs [p190, Cdc42 GAP and PTPL1-associated RhoGAP]. The assay detected activities associated with purified recombinant GEFs and GAPs, cell lysates expressing exogenous proteins, and immunoprecipitates of endogenous Vav1 and p190. The results demonstrate that the split luciferase system provides an effective sensitive alternative to radioactivity-based assays for detecting GTPase regulatory protein activities and is adaptable to a variety of assay conditions.

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