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Cited by 63

The DOI matches its Crossref record; 140 of the 140 references it cites were found in a registry or an index.

The Vav GEF Family: An Evolutionary and Functional Perspective

Rodríguez-Fdez, Sonia, Bustelo, Xosé R.·2019·Cells
DOI 10.3390/cells8050465PMC PMC6562523
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Abstract

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.

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Figure 1 Structure, regulation, effector functions, and evolution of Vav proteins. (A) Depiction of the structure, the intramolecular interactions that control the signaling output (top), the main regulatory phosphosites (using the amino acid sequence corresponding to mouse Vav1), and the main downstream pathways (bottom) of mammalian Vav proteins. Abbreviations for the domains and proteins depicted in the figures have been described in the main text. (B) Evolution of PTKs, Rho GTPases, and Rho GEFs. The size of the circles is proportional to the number of members present in the indicated protein families and taxonomic groups. Please note that in some species (e.g., amoebozoans, plants) there is tyrosine kinase activity carried out nonspecifically by serine/threonine protein kinases (gray circles). Proteins with equivalent function but with non-metazoan domain combinations are also present in other species (gray circles). In the case of PTKs, the percentage of transmembrane (light red color) and cytoplasmic (light brown color) versions is depicted in the figure. For Rho GEFs, the percentage of members belonging to the DH and Dock subclasses is indicated using light red and light brown colors, respectively. In the case of Rho GTPases and Rho GEFs, the presence of specific family members (Rho, Rac, Cdc42, Vav) is indicated by small light red dots. This figure integrates information from previous publications [19,20,21,22,23,24,25,26] and manual curation procedures using UniProt-archived data.
Figure 1 Structure, regulation, effector functions, and evolution of Vav proteins. (A) Depiction of the structure, the intramolecular interactions that control the signaling output (top), the main regulatory phosphosites (using the amino acid sequence corresponding to mouse Vav1), and the main downstream pathways (bottom) of mammalian Vav proteins. Abbreviations for the domains and proteins depicted in the figures have been described in the main text. (B) Evolution of PTKs, Rho GTPases, and Rho GEFs. The size of the circles is proportional to the number of members present in the indicated protein families and taxonomic groups. Please note that in some species (e.g., amoebozoans, plants) there is tyrosine kinase activity carried out nonspecifically by serine/threonine protein kinases (gray circles). Proteins with equivalent function but with non-metazoan domain combinations are also present in other species (gray circles). In the case of PTKs, the percentage of transmembrane (light red color) and cytoplasmic (light brown color) versions is depicted in the figure. For Rho GEFs, the percentage of members belonging to the DH and Dock subclasses is indicated using light red and light brown colors, respectively. In the case of Rho GTPases and Rho GEFs, the presence of specific family members (Rho, Rac, Cdc42, Vav) is indicated by small light red dots. This figure integrates information from previous publications [19,20,21,22,23,24,25,26] and manual curation procedures using UniProt-archived data.CC BY · PubMed Central
Figure 2 Evolution of the “body plan” of Vav family proteins. Depiction of the structure of Vav proteins in representative organisms of both the choanozoan (in gray) and metazoan (salmon-color gradient) phyla. UniProt accession codes are indicated for each protein.
Figure 2 Evolution of the “body plan” of Vav family proteins. Depiction of the structure of Vav proteins in representative organisms of both the choanozoan (in gray) and metazoan (salmon-color gradient) phyla. UniProt accession codes are indicated for each protein.CC BY · PubMed Central
Figure 3 “Exotic” forms of Vav proteins found in invertebrate species.Depiction of the structure of Vav proteins in the indicated organisms (Uniprot accession codes are indicated for each protein). MRP-S33, mitochondrial ribosomal protein S33; Tm, transmembrane domain; CLECT, C-type lectin or carbohydrate-recognition domain; KR, kringle domain; LIM, zinc-binding domain present in Lin-11, Isl-1, and Mec-3; HOX, homeobox; EHN, epoxide hydrolase N-terminus; ABHD1, abhydrolase domain-containing 1. Please note that the relevance of the “exotic” version detected in Trichuris suis is still unclear since there is discrepancy in the overall structure of the locus in three independent animals of this species that have been sequenced. In the rest of species, they do seem to represent bona-fide loci.
Figure 3 “Exotic” forms of Vav proteins found in invertebrate species.Depiction of the structure of Vav proteins in the indicated organisms (Uniprot accession codes are indicated for each protein). MRP-S33, mitochondrial ribosomal protein S33; Tm, transmembrane domain; CLECT, C-type lectin or carbohydrate-recognition domain; KR, kringle domain; LIM, zinc-binding domain present in Lin-11, Isl-1, and Mec-3; HOX, homeobox; EHN, epoxide hydrolase N-terminus; ABHD1, abhydrolase domain-containing 1. Please note that the relevance of the “exotic” version detected in Trichuris suis is still unclear since there is discrepancy in the overall structure of the locus in three independent animals of this species that have been sequenced. In the rest of species, they do seem to represent bona-fide loci.CC BY · PubMed Central
Figure 4 Conservation of the main phosphosites involved in Vav family regulation.For comparison, we include the structure and positions of the regulatory phosphosites of mouse Vav1 (top). Numbers (red boxes) indicate the position in the primary sequence of the indicated Vav family protein of the regulatory phosphosites that were previously identified in mammalian Vav1 (blue boxes).
Figure 4 Conservation of the main phosphosites involved in Vav family regulation.For comparison, we include the structure and positions of the regulatory phosphosites of mouse Vav1 (top). Numbers (red boxes) indicate the position in the primary sequence of the indicated Vav family protein of the regulatory phosphosites that were previously identified in mammalian Vav1 (blue boxes).CC BY · PubMed Central
Figure 5 The gain and loss of Vav family members in vertebrates. (A) Phylogenetic tree of Vav family proteins (left). Proteins containing DH and SH2 domains were obtained from the UniProt database and the phylogenetic tree reconstructed using the maximum-likelihood method. Node colors indicate if the protein belongs to the single Vav family group (gray color) or the vertebrate Vav1 (orange color), Vav2 (green color) or Vav3 (purple color) branch. The lamprey (Petromyzon marinus) Vav1/3-like protein node has been highlighted in light brown. The color code used for each phylogenetic clade is shown on the light blue box (right). (B) Number of Vav family genes conserved in each vertebrate clade. 1R and 2R indicate the two rounds of whole-genome duplications that took place before the divergence of jawless and cartilaginous fish, respectively. 3R and 4R indicate the lineage-specific whole-genome duplication events associated with the origin of the ancestor of most teleost fish and salmonids, respectively. Time scale is indicated at the bottom (Mya; million years ago). (C) Variability in the number of Vav family proteins in avian clades. Species with either high-coverage or fully sequenced genomes are underlined. Cases associated with the loss of Vav1 and/or Vav3 genes in some species are indicated with asterisks. Proteins colored in gray indicate that the Vav family member has been lost in a high percentage of species of the indicated group. Avian phylogeny has been established as described elsewhere [105]. Time scale is indicated at the bottom.
Figure 5 The gain and loss of Vav family members in vertebrates. (A) Phylogenetic tree of Vav family proteins (left). Proteins containing DH and SH2 domains were obtained from the UniProt database and the phylogenetic tree reconstructed using the maximum-likelihood method. Node colors indicate if the protein belongs to the single Vav family group (gray color) or the vertebrate Vav1 (orange color), Vav2 (green color) or Vav3 (purple color) branch. The lamprey (Petromyzon marinus) Vav1/3-like protein node has been highlighted in light brown. The color code used for each phylogenetic clade is shown on the light blue box (right). (B) Number of Vav family genes conserved in each vertebrate clade. 1R and 2R indicate the two rounds of whole-genome duplications that took place before the divergence of jawless and cartilaginous fish, respectively. 3R and 4R indicate the lineage-specific whole-genome duplication events associated with the origin of the ancestor of most teleost fish and salmonids, respectively. Time scale is indicated at the bottom (Mya; million years ago). (C) Variability in the number of Vav family proteins in avian clades. Species with either high-coverage or fully sequenced genomes are underlined. Cases associated with the loss of Vav1 and/or Vav3 genes in some species are indicated with asterisks. Proteins colored in gray indicate that the Vav family member has been lost in a high percentage of species of the indicated group. Avian phylogeny has been established as described elsewhere [105]. Time scale is indicated at the bottom.CC BY · PubMed Central

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  1. Ksionda, 2012, Mechanism and function of Vav1 localisation in TCR signalling, J. Cell Sci., 125, 5302

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Metadata

Authors
Rodríguez-Fdez, S., & Bustelo, X. R.
Affiliations
Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, E37007 Salamanca, Spain
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2019-05-16
Volume
8
Issue
5
Pages
465
ISSN
2073-4409
DOI
10.3390/cells8050465
PMC
PMC6562523
Cited by
63
References
140
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Consejería de Educación, Junta de Castilla y León (CSI049U16, CLC–2017–01)
  • Ministerio de Ciencia e Innovación (SAF2015–64556–R, BES–2013–063573)
  • Fundación Ramón Areces (N/A)
  • Fundación Científica Asociación Española Contra el Cáncer (GC16173472GARC)

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