Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Vav Family

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_513

Synonyms

Historical Background

The Vav family is a group of signal transduction proteins that work as phosphorylation-dependent GDP/GTP exchange factors (GEFs) for GTPases of the Rho subfamily as well as adaptor molecules. This family is composed of three members in vertebrates (Vav1, Vav2, and Vav3) and single representatives in invertebrates (known generically as Vav). By contrast, Vav proteins are missing in unicellular organisms and plants. The first member of this family was discovered in Mariano Barbacid’s lab in 1989 due to the spurious stimulation of its transforming activity during transfections of a human tumor-derived genomic DNA in rodent fibroblasts. Since it was the sixth oncogene isolated in that lab, it received the name of the sixth letter of the Hebrew alphabet (Vav). The product encoded by the proto-oncogene was designated as Vav or, taken into consideration its molecular weight and the notation of oncogenes at that time, p95 vav . Vav2 and Vav3 proteins were subsequently identified in human and rodent species between 1995 and 2000. Since then, p95 vav has been referred to as Vav1 to keep a consistent nomenclature within the family. The explosion of gene data derived from current genome sequencing efforts has led to the discovery of the rest of Vav family members present in vertebrate and invertebrate species in the last decade.

The function of Vav1 could not be easily inferred upon its isolation, since many of the currently known structural domains had not been characterized at that time. The concept that Vav1 was a signal transduction molecule implicated in protein tyrosine kinase-dependent routes crystallized in 1992 upon the pivotal discovery that this protein contained Src-homology (SH) regions and could become tyrosine phosphorylated by both mitogenic and antigenic receptors (Bustelo and Barbacid 1992; Bustelo et al. 1992). The discovery that Vav1 was a phosphorylation-dependent Rho GEF was reported 5 years later (Crespo et al. 1997). This final step led to an integrated view of the mechanisms mediating the activation of Vav proteins during physiological and oncogenic conditions. However, a complete view of the mechanism by which the activity of these proteins is regulated by tyrosine phosphorylation could not be achieved until very recently (Barreira et al. 2014). Since 1994, extensive work using model organisms demonstrated that these proteins modulate important biological processes in vivo in species ranging from C. elegans to mice. In this chapter, we will provide an overall view of the current knowledge about the structure, regulatory mechanisms, and functions of these proteins. Readers can find further information elsewhere (Bustelo 2008; Bustelo and Couceiro 2008; Bustelo 2014).

Structure

All vertebrate and prochordate Vav family members contain eight different structural domains: a calponin-homology (CH) region, an acidic (Ac) domain, a Dbl-homology region (DH), a pleckstrin-homology (PH) domain, a zinc finger region of the C1 subtype (C1), two SH3 domains, and an SH2 region (Fig. 1). The family members from invertebrate species lack the most N-terminal SH3 region (Fig. 1). Other regulatory sequences are present in some family members, such as the proline-region (PRR) found in Vav1 proteins. Vav family genes can generate a number of Vav isoforms by differential splicing (Fig. 1). The functional significance of these alternative isoforms is currently unknown. Although all the domains present in Vav proteins are commonly found in many signaling molecules, Vav proteins are the only ones that contain a DH-PH-C1 cassette and an SH2 region. This is due to their quite specific requirements for catalysis (see Section “Biological Activity”) and activation (see Section “Regulation of Biological Activity”), respectively.
Vav Family, Fig. 1

Structure of Vav family members and main isoforms. The structure of D. melanogaster (Dm) and mammalian Vav family members and isoforms are depicted. In addition to the structural domains present in those proteins, the six regulatory phosphorylation sites present in the Ac, C1, and C-terminal SH3 domains of Vav family proteins are shown. The length of the insertions found in Vav2 isoforms is also indicated. Aac amino acid. The abbreviations for the indicated domains have been introduced in the main text

Current evidence suggests that each structural domain has multifunctional roles, participating in intramolecular regulatory actions, protein-protein interactions, and/or effector roles. The CH, Ac, and most C-terminal SH3 regions participate in phosphorylation-dependent intramolecular interactions that regulate the function of Vav proteins (see below, Section “Regulation of Biological Activity”) and, at the same time, establish physical interactions with other proteins (Fig. 2). Although the functional significance of most of those interactions is still unclear, some of them appear to be important for either the activation of specific Vav family members (i.e., APS contributes to Vav3 activation; Fig. 2) or the assembly of downstream, T cell-specific functions that are engaged in a catalysis-independent manner such as, for example, the CH-mediated stimulation of the nuclear factor of activated T cells (NFAT) (i.e., Calmodulin, Fig. 2). The DH region is the catalytic domain that stimulates GDP/GTP exchange on Rho proteins. However, it can also participate in the formation of heteromolecular interactions that contribute to either the activation (p67Phox) or subcellular localization (Rap1) of specific Vav family members in some specific cellular contexts. The Vav family PH and C1 domains form a structural unit with the DH domain that favors the formation of a catalytic competent conformation of the DH region (Movilla and Bustelo 1999; Chrencik et al. 2008; Rapley et al. 2008). The most N-terminal SH3 domain and an adjacent PRR participate in the formation of protein-protein interactions with Grb2 family members (Grb2, Grb3-3; Fig. 2). The interaction with Grb2 is important to allow the association of Vav proteins with specific transmembrane proteins. The Vav family SH2 domains are crucial for the activation of Vav family proteins during signal transduction, because they allow the interaction of the inactive Vav proteins with a wide spectrum of activated transmembrane and cytoplasmic tyrosine kinases. In addition, they favor the interaction of active Vav proteins with cytoplasmic proteins (Slp76, Blnk) that participate in their signal transduction pathways (Fig. 2). The most C-terminal SH3 domain participates in the formation of extensive heteromolecular interactions with PRR-containing proteins (Fig. 2). Some of those SH3 partners facilitate the translocation of Vav proteins (Dynamin 2) or participate in the catalytic-independent effector functions of these proteins (Sam68). However, the functional significance of many of the Vav family C-terminal SH3 binding partners remains to be determined. Interestingly, the Vav C-terminal SH3 region is also the docking site for proteins encoded by viral pathogens such as the human immunodeficiency virus (HIV, v-Nef protein) and γ-herpesvirus (M2 protein) (Fig. 2). The interaction of those two proteins allows the spurious, stimulus-independent activation of some Vav family proteins during viral infections. It is likely that the Vav structural domains will participate in additional heteromolecular interactions, because Vav proteins can coimmunoprecipitate with a large collection of signaling proteins (Fig. 2). Although the function of most of those interacting molecules in the context of Vav-dependent routes is still unknown, some of them have been shown to act as upstream kinases (Alk, Bcr-Abl, Jak), facilitators of the translocation of Vav proteins to the plasma membrane (CD44v3, Dip, p120Cat, Pyk2, Itk), and effector molecules (p85 PI3-K , PKCθ, phospholipase-γ (PLC-γ) family members).
Vav Family, Fig. 2

Vav binding partners. Proteins playing positive, negative, and effector roles are depicted in green, red, and blue, respectively. Note however that some regulatory proteins also play downstream roles (i.e., Blnk, Slp76). Proteins with unclear function in the Vav route are shown in black. Molecules identified only in either Vav2 or Vav3 are underlined. Proteins that bind to Vav proteins in coimmunoprecipitation experiments through uncharacterized mechanisms are indicated on the right. The structural domains and type of interactions are also indicated. PTB phosphotyrosine binding domain, pY phosphorylated tyrosine residue, NC not characterized

It is conceivable that all Vav family members will share most of those interactions, although current evidence indicates that some selectivity must exist. For example, M2 and v-Nef interact with Vav1 and Vav2 but not with Vav3. Likewise, dynamin 2 binds to Vav1 but not to the other two mammalian Vav family members. A detailed, side-by-side comparison of the signaling properties of all Vav family members is still needed in order to fully understand the level of overlap and phylogenetic conservation of the Vav family interactomes.

Expression

Vav1 is primarily expressed in hematopoietic cells both in the embryonic and adult periods. Vav2 and Vav3 are also expressed in hematopoietic cells but, unlike the case of Vav1, also show high levels of expression in nonhematopoietic tissues. In C. elegans Vav is detected in contractile organs such as the pharynx, proximal gonad, intestine, body wall muscle, and vulval epithelia. D. melanogaster Vav is ubiquitously expressed during early embryos and accumulates in both the central nervous system and invaginating midgut at later embryonic stages. These data indicate that Vav1 is, so far, the Vav family member with a more restricted pattern of expression.

Biological Activity

The main known function of Vav family proteins is to act as GEFs for Rho subfamily GTPases (Crespo et al. 1997; Schuebel et al. 1998; Movilla and Bustelo 1999). This activity favors the rapid shift of those GTP-binding proteins from the inactive (GDP-bound) to the active (GTP-bound) state during signal transduction (Fig. 3). Vav proteins promote the activation of Rac subfamily GTPases (e.g., Rac1, RhoG) and, to a lower extent, of Rho (e.g., RhoA) subfamily proteins in vitro. There is discrepancy about the possible activation of Cdc42 among different reports. Unlike other activators of Rho proteins whose enzyme activity relies exclusively within the catalytic DH region, the catalysis of nucleotide exchange on GTPase substrates requires the entire DH-PH-C1 cassette (Movilla and Bustelo 1999).
Vav Family, Fig. 3

Vav family proteins work as Rho GEFs and adaptor proteins. Inactive and active conformations of the GTPase substrates are indicated in light blue and red, respectively. GAPs GTPase-activating proteins that favor the transition of Rho proteins from the active to the inactive state, Pi inorganic phosphate released upon GTP hydrolysis

Consistent with their role as Rho GEFs, Vav proteins induce Rho-dependent biological responses in tissue culture such as F-actin polymerization, invasiveness, motility, integrin-mediated adhesion, cell cycle transitions, or metastasis. They also stimulate canonical signaling pathways located downstream of Rho GTPases such as p21-activated kinases (Pak), c-Jun N-terminal kinase (JNK), the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), activator protein 1 (AP1) family proteins, and serum responsive factor (SRF). However, they can also promote the stimulation of downstream pathways in catalysis-independent manners through other domains such as, for example, the CH-mediated stimulation of NFAT in lymphocytes (Fig. 3). The crucial importance of Vav family-dependent pathways in vivo has been demonstrated by analyzing the phenotypes of single or compound null mutations in model organisms. In agreement with its hematopoietic-specific pattern of expression, it has been shown that mouse Vav1, either alone or in combination with the rest of Vav family members, plays crucial roles in the development, selection, and effector functions of lymphocytes (Table 1). Signaling defects also have been found in a large variety of hematopoietic cells, including platelets, neutrophils, macrophages, mast cells, natural killer cells, and dendritic cells (Table 1). In the case of Vav2- and Vav3-deficient mice, defects have been also observed outside the hematopoietic system. Those include dysfunctions in axon guidance, angiogenesis, bone remodeling, cerebellar development, blood pressure regulation, and metabolic disease (Table 1). The signaling dissection of those defects indicates that Vav proteins are essential for a large number of signaling responses induced by antigen receptors in hematopoietic cells. Those include: (i) T cell and B cell receptor responses that contribute to cytoskeletal rearrangement, formation of lymphocyte/antigen presenting cell contacts, and lymphocyte responsiveness; (ii) signaling diversification events such as the stimulation of phoshatidylinositol-3 kinase (PI3-K)/Akt-, PLCγ-, Ras/Erk-, PKC-, PKD-, and PLD-dependent routes; (iii) activation of downstream transcriptional factors such as NFAT, NFκB, SRF, and AP1 family proteins; (iv) expression of lymphocyte surface markers and cytokines; and (v) modulation of cell cycle regulators and survival pathways. In nonhematopoietic cells, Vav proteins have been shown to be important for Eph receptor signaling during angiogenesis and axon guidance, Rac-mediated GABAergic wiring within the brainstem ventrolateral medulla, and for proper assembly of nitric oxide-dependent signals in vascular smooth muscle cells. In invertebrates, C. elegans Vav is important for the rhythmic behavior of a number of tissues, leading to improper pharyngeal contractility as well as defective ovulation and defecation activities. This leads to larval lethality when its locus is disrupted genetically in this nematode (Table 2). D. melanogaster Vav is important for neuronal axon guidance and proper locomotor coordination (Table 2). These phenotypes are in agreement with both the expression patterns of these two Vav family members in those two species and their role as Rac-specific GEFs. Although there is signaling and genetic evidence indicating that the Vav catalysis-independent pathways play important roles in some cellular contexts (i.e., PLCγ and NFAT activation in T cells), there is common agreement that the main signaling flux mediated by these proteins is catalysis-dependent.
Vav Family, Table 1

Phenotypes observed in Vav family knockout mice

Cell type

Vav1 −/−a

Vav2 −/−

Vav3 −/−

Vav1−/−; Vav2−/−

Vav1−/−;Vav3−/−

Vav2−/−;Vav3−/−

Vav1−/−; Vav2−/−;Vav3−/−

T cells

Thymocytes

Defective developmental transitions

Normal

Normal

Similar to Vav1−/− mice when tested

Aggravation of Vav1−/− phenotype

Normal

Aggravation of Vav1−/−; Vav3−/− phenotype

Defective positive and negative selection

T cell lymphomas at older ages

Mature

Reduced numbers

Normal

Normal

Similar to Vav1−/− mice when tested

Aggravation of Vav1−/− phenotype

Normal

Aggravation of Vav1−/−;Vav3−/− phenotype

Defective BCR responses

Defective recruitment of activated T cells in peripheral tissues

B cells

Immature

Absence of peritoneal B1 cells

Normal

Normal

Blockage in B cell maturation

NAb

NA

Blockage in B cell maturation

Mature

Defective maturation in periphery

Defective BCR-dependent proliferation under suboptimal conditions of stimulation

 

Reduced numbers

  

Defects in peripheral B cell survival

Defective T cell-dependent responses

Defective maturation in periphery

Defective responses to chemokine receptors

Defective BCR-dependent proliferative and adhesion responses

Defective CD180- and LPS-dependent responses

Defective CD180-dependent responses

Platelets

Normal

Normal

Normal

NA

Defects in platelet aggregation and spreading

NA

Similar to Vav1−/−; Vav3−/− mice

Neutrophils

Crawling and migration defects

Normal

Normal

NA

Defects in integrin-dependent adhesion, spreading and phagocytosis

 

Lack of oxidative burst

Defective extravasation in inflamed vasculature

Suboptimal activation of IgG/FcγR-dependent hemorrhage and edema in lung and skin

Defective interstitial transit to sites of bacterial infection

Defective responses to nosocomial organisms

Macrophages

No defects

No defects

No defects

NA

Defective complement-mediated phagocytosis

NA

Similar to Vav1−/−; Vav3−/− mice

Mast cells

Defective degranulation and cytokine production

NA

NA

NA

NA

NA

NA

Suboptimal anaphylactic responses

Natural killer cells

Defective natural and antitumor cytotoxic responses

NA

NA

NA

NA

Defective DAP12- and FcRy-dependent cytotoxic responses

Impaired PAP10-, DAP12-, and FcRγ-dependent killing

Defective responses induced by the DAP10 receptor

Dendritic cells

Defective integrin-mediated adhesion and podosomal dynamics

NA

NA

NA

NA

NA

Defective antigen presentation due to improper function of DAP12 and FcRγ receptors

Cardiovascular system

Normal

Hypertension

Hypertension

NA

NA

Hypertension

NA

Protection against tissue fibrosis induced by angiotensin II-dependent hypertension

Renocardiovascular disease

Renocardiovascular disease

Renocardiovascular disease

Defective nitric oxide-dependent Vasodilatation responses of vascular smooth muscle cells

Defective late maturation steps of osteoclasts

Defective nitric oxide-dependent Vasodilatation responses of vascular smooth muscle cells

The phenotype is the combination of those found in single knockout animals. There is no aggravation of phenotype

Metabolic system

NA

Normal

Metabolic syndrome under chow diet conditions

Normal

NA

NA

NA

Nervous system

Normal

Hydrocephaly

Hydrocephaly

NA

NA

Axon guidance of retinal ganglion cells

GABAergic innervation defects in ventrolateral medulla

Cerebellar development and motor coordination defects

Combination of phenotype observed in Vav3-deficient mice

Other features not analyzed

GABAergic innervation defects in ventrolateral medulla

Bone

Normal

Normal

Defective osteoclasts function

NA

NA

NA

NA

Defective bone remodeling

Endothelial cells

NA

NA

NA

NA

NA

Angiogenesis defects

NA

Intestine

NA

NA

NA

NA

NA

NA

Minor defects in cecal enterocytes

Ulcerative lesions in intestine in old animals

aThe genotypes of animals analyzed are indicated

bNA not analyzed

Vav Family, Table 2

Phenotypes derived from the alteration of the function of invertebrate species Vav family members

Organism

Phenotype

C. elegans

Gain-of-functiona

Hypercontracted muscles

Loss-of-functionb

Feeding problems during early development

Larval lethality

Defective pharyngeal contractility

Defective and arrhythmic ovulation and defecation cycles

Increased activity of Lin-12/Notch, leading to the generation of hermaphrodites with multiple pseudovulvae

D. melanogaster

Gain-of-function

Defective dorsal closure

Problems in myoblast fusion

Defective migration of caudal visceral mesodermal cells

Dysfunctional tracheal development

Loss-of-function

Semilethal embryonic lethality, some of which can be due to improper eclosion of flies from eggs due to locomotor deficits

Flies that scape embryonic lethality display severe locomotor defects and a “shaky” phenotype

Axon guidance defects

In combination with loss of Trio (another Rac1 GEF), embryonic patterning defects and aggravation of the axon guidance defects found in embryos lacking either Vav or Trio

In combination with loss of Sos1 (a Rac1/Ras GEF), aggravation of the axonal problems found in the absence of Vav

aGain-of-function refers to phenotypes obtained upon the ectopic expression of oncogenic versions of these proteins in the respective species

bLoss-of-function refers to phenotypes derived from animals in which the Vav family genes have been inactivated by genetic techniques

Regulation of Biological Activity

The main regulatory control of Vav family proteins is the modulation of their catalytic and adaptor activities by direct tyrosine phosphorylation (Crespo et al. 1997; Schuebel et al. 1998; Movilla and Bustelo 1999; Barreira et al. 2014). Recent biochemical and structural analyses indicate that the inactive, nonphosphorylated state of these proteins is maintained through extensive interactions among: (i) the CH domain and the PH, DH, and two tyrosine residues (Y142 and Y160, amino acid numbers are given for Vav1) present in the Ac region, (ii) the Ac region with the PH domain, (iii) a tyrosine residue of the Vav Ac region (Y174) with the GTPase binding domain of the Vav DH region, and (iv) interactions of two regions of the C-terminal SH3 domain (outside the canonical PRR binding site) with the DH and PH domains (Fig. 4) (Yu et al. 2010; Barreira et al. 2014). All these interactions induce cooperatively a “closed” conformation of Vav1 proteins that is incompatible with the binding of GTPase substrates to the catalytic region and, most likely, the acquisition of a signaling compatible spatial distribution of the N-terminal CH domain (Fig. 4). The phosphorylation of the phosphosites present in the Ac, C1, and C-terminal SH3 domain leads to the release of those intramolecular inhibitory interactions and the stimulation of the catalytic and adaptor activities of the protein (Fig. 4) (Barreira et al. 2014). This is also associated with a change in the spatial structure of the DH region that, possibly, contributes to the stabilization of the interaction of the downstream GTPase (Yu et al. 2010). Biochemical and signaling evidence indicates that this mechanism is conserved in all Vav family members studies so far, including C. elegans and D. melanogaster Vav proteins (Barreira et al. 2014; Bustelo 2014).
Vav Family, Fig. 4

Schematic representation of the phosphorylation-dependent activation of Vav proteins during physiological conditions. In the inactive state (left), Vav proteins are in a closed conformation incompatible with catalysis-dependent and independent signaling output. Upon association with protein tyrosine kinases, Vav proteins become phosphorylated (red balls) on six phosphosites (open triangles) present in the Ac, C1, and C-terminal SH3 domains. This leads to the opening of the molecule and the stimulation of Vav-regulated activities. Active forms of Vav proteins return to the inactive conformation by dephosphorylation by protein tyrosine phosphatases (PTPase). The model is still hypothetical and based on data gathered using biochemical and structural techniques. However, the inhibitory structure mediated by the CH-Ac region has been solved using crystallographic methods (Yu et al. 2010). 2 SH2, 3 N N-terminal SH3, 3C C-terminal SH3, p phosphorylated residue. Other abbreviations have been introduced in main text

Vav proteins are also controlled by other regulatory steps in vivo. The most important is the translocation of the proteins from the cytosol to the plasma membrane, a step required for the interaction with both upstream tyrosine kinases and membrane-localized downstream effectors. In nonhematopoietic cells, the membrane translocation of Vav family proteins usually involves a single event mediated by the direct interaction of the Vav SH2 region with the autophosphorylated tyrosine kinase receptors. Once bound to them, Vav proteins become transphosphorylated by the associated kinase (Fig. 5a). In the case of lymphocytes, the translocation of Vav proteins usually entails their interaction with membrane-localized proteins. Those can be either transmembrane coreceptors (CD28, CD19) or plasma membrane inner leaflet-associated adaptor molecules (linker for activation of T cells or Lat) (Fig. 5b). The association with coreceptors is established by either direct physical contact (i.e., the association of the Vav SH2 domain with a phosphorylated residue located on the cytoplasmic tail of CD19) or using bridge molecules (i.e., the binding of Gbr2 to the CD28 coreceptor) (Fig. 5b). The association with membrane-anchored adaptors entails the use of signaling adaptors such as the Vav-binding proteins Grb2, Slp76, Blnk, Pyk2, and Itk (Bustelo 2014).
Vav Family, Fig. 5

Examples of the interaction of Vav proteins with transmembrane receptors. (a) Direct interaction of Vav proteins with autophosphorylated receptors with intrinsic tyrosine kinase activity. The binding and subsequent phosphorylation-mediated activation steps of Vav proteins are indicated. (b) Vav proteins can establish direct physical interactions with intracellular tyrosine kinases of the Syk-Zap70 family (center) and with lymphoid coreceptors (i.e., CD19, left). Vav proteins can also interact with other coreceptors (i.e., CD28) via Vav binding proteins such as Grb2 (right). In a and b, phosphorylation sites are indicated as red spheres. The rest of Vav domains and residues depicted in this figure have been described in the legend to Fig. 4. Note that for the sake of simplicity two types of coreceptors have been included together in this figure despite the fact that they are not coexpressed in the same lymphoid cell types. We also have included in panel b only the binding but not the subsequent activation step for simplicity. The translocation of Vav proteins can be also mediated by other molecules as indicated in the main text. ITAM immunoreceptor tyrosine-based activation motif, PM plasma membrane, PTK protein tyrosine kinase

Current evidence suggest that the biological activity of Vav proteins can be regulated by additional posttranslational mechanisms including caspase-dependent cleavage during anergic T cell conditions, arginine methylation, and, possibly, lysine acetylation. The physiological significance of all those posttranslational modifications remains to be fully determined. Recent observations indicate that the levels of some Vav family mRNAs (human Vav3, C. elegans Vav) can be regulated by microRNAs.

Implication of Vav Family Proteins in Pathological States

Mutations that eliminate the intramolecular inhibitory mechanism that controls the latent enzyme activity of these proteins originate Vav family proteins that are oncogenic when expressed in rodent fibroblasts (Fig. 6a). Similar mutations have been also described in C. elegans and D. melanogaster Vav family genes, leading to tumorigenesis and developmental problems in the respective species (Table 2). Interestingly, recent sequencing efforts have found point, stop, and translocation mutations in Vav1 in T cell leukemia/lymphoma, peripheral T cell leukemia, and lung cancer (Kataoka et al. 2015; Boddicker et al. 2016; Campbell et al. 2016; Abate et al. 2017) (Fig. 6b). Many of these mutations target key regulatory sites, although whether they work as oncogenic drivers is as yet unknown. Despite the foregoing data, current information indicates that the in vivo deregulation of Vav family proteins tends to occur more frequently through changes in either the expression or phosphorylation levels of the wild-type proteins. For example, Vav1 is detected overexpressed in subsets of pancreatic, lung, and hematopoietic tumors. Higher levels of Vav1 expression, linked to the presence of an intronic single nucleotide polymorphism on its gene, seem to be associated with human cohorts with a higher tendency to develop multiple sclerosis. Hyperphosphorylation of Vav family proteins has been observed in cancer cells expressing oncogenic versions of protein tyrosine kinases (i.e., Alk, Bcr-Abl) or, alternatively, displaying active, mitogen-dependent autocrine loops. Genetic data gathered from animal models have demonstrated that Vav proteins do have proactive roles in the development of certain cancer types, including skin papillomas, breast cancer, and hematopoietic tumors (Chang et al. 2012; Citterio et al. 2012; Martin et al. 2013; Menacho-Marquez et al. 2013). Finally, it has been observed that Vav1 and Vav3 can become upregulated in lymphocytes upon infection of viral pathogens encoding Vav family-interacting molecules such as v-Nef and M2. This viral-dependent activation is important for the infectivity cycle and the establishment of the latency stage of HIV and γ-herpesvirus, respectively. On the other side of the coin, a blockage in activation of Vav1 has been detected in anergic T cells via a caspase-dependent proteolysis. The actual significance of those inhibitory events has not been fully studied so far. Taken together, these results suggest that Vav proteins may play important roles in a number of high-incidence illnesses such as cancer, autoimmune disease, and viral pathogenesis.
Vav Family, Fig. 6

Oncogenic activation of Vav proteins. (a) Scheme of wild type (WT) and oncogenic versions of Vav1. The first oncogenic version described was a truncated Vav1 protein lacking the first 66 N-terminal amino acids (protein 2). Similar mutations have been described in other Vav family members. (b) Example of Vav1 point mutations found in T cell leukemia/lymphoma (Kataoka et al. 2015). Only mutations that have been found at least twice are shown. Each circle indicates a mutation found in an independent patient

Summary

Despite the progress made during these last 30 years, many challenges lie still ahead in this field. For example, it is not known as yet the role of other posttranslational modifications on Vav activity. There is also a lack of information regarding the functional significance of many of the Vav-interacting proteins identified to date or, in a related topic, the relative contribution of both GTPase-dependent and independent routes to the biological responses regulated by those proteins. Another issue of interest is the level of functional redundancy and signaling specificity existing among the three mammalian Vav family members. In this regard, current data indicate that Vav proteins have both unique and overlapping functions depending on the cell type and/or biological response analyzed. However, these analyses have been done in a limited number of cell types, so a comprehensive view of the level of functional redundancy among Vav family members is still missing. Finally, there is still very scant information about the actual implication of Vav proteins in pathological states and, as consequence, no solid information is available about the possible interest of these proteins as drug targets to treat human disease. The available collection of animal models for this protein family will be an important tool in the near future to address that question. Collectively, this future work will give a holistic and, hopefully, final picture of the implication of this important protein family in physiological and pathological responses.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) and Centro de Investigación del CáncerCSIC-University of SalamancaSalamancaSpain