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Review
. 2000 Mar;20(5):1461-77.
doi: 10.1128/MCB.20.5.1461-1477.2000.

Regulatory and signaling properties of the Vav family

X R Bustelo  1
Affiliations
Review

Regulatory and signaling properties of the Vav family

X R Bustelo. Mol Cell Biol. 2000 Mar.
No abstract available

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Figures

FIG. 1
FIG. 1
(A) Structures of Vav family proteins. The tyrosine residue involved in Vav downmodulation (Y174) is shown. The alternative sequences of Vav2 generated by alternative splicing of its hnRNA are indicated by A, B, and C. Deletions or insertions of sequences found in the CelVav protein are illustrated by using empty spaces and solid boxes, respectively. The lack of the two cysteine residues in the C terminus of the CelVav ZF is indicated by a gray box. SH3L is the region with low resemblance to SH3 domains present in CelVav. (B) Oncogenic mutations found in Vav family members. WT, wild type. An asterisk indicates the Y174F mutation. Amino acid numbers are shown at the bottom of each panel.
FIG. 2
FIG. 2
Types of interaction between Vav and upstream elements during the signaling of membrane PTKs (A), cytokine receptors (B), the TCRαβ (C), and the BCR (D). PTK, protein tyrosine kinase; L, ligand; Ag, antigen; KD, kinase domain; P, phosphorylated tyrosine residue; N, proximal SH3 domain; C, distal SH3 domain. Transmembrane domains are indicated by open boxes, immunoreceptor tyrosine-based activation motif-containing molecules are shown as boxes with horizontal lines, SH2 domains are shown as solid boxes, SH3 domains are shown as dotted circles, and the rest of the N-terminal domains of Vav are shown as a shaded box. The proteins included are not shown to scale. The two possible transmembrane ligands for CD28 (CD80 and CD86) are indicated. The ligand for CD19 is as yet unknown, although it is believed that it binds to complement (C3) with the help of a second coreceptor, CD21 (43).
FIG. 3
FIG. 3
Structures of regulatory elements of the Vav pathway. A and B, interdomains A and B; KD, kinase domain; JH, Jak homology; KD-L, kinase domain-like; TM, transmembrane region; PS, prenylation site; PR, proline-rich region; PTPaseD, phosphatase domain; 4H, four-helix bundle; EF, EF hand. The phosphorylation sites recognized by the Vav SH2 domain in Syk, Zap70, Slp76, and BLNK are indicated (the sites in BLNK have not been formally identified). Amino acid numbers are shown at the bottom of the figure.
FIG. 4
FIG. 4
(A) Model for the synergy observed between Vav and Slp76. SH2 domains are indicated by closed boxes, SH3 domains are shown as dotted circles, the Vav DH domain is depicted as a shaded box, and the N-terminal domains of Slp76 are shown as an open box. PPPP, proline-rich region; P, phosphorylated tyrosine residues. (B) Possible points of functional interaction among the Vav, Ras, and Slp76 pathways. For simplicity, only one of the effector molecules of Rac (PAK) has been represented. The exact downstream elements of Vav leading to NF-AT activation have not been identified. The same applies to the pathways of Slp76 leading to ERK, PLC-γ1, and NF-AT activation.
FIG. 5
FIG. 5
Schematic representation of thymocyte development. The processes affected by the vav gene knockout are indicated. Defects observed in other signaling proteins involved in the Vav pathways have been included for comparison. Inhibition or upregulation of a given T-cell response is indicated by blunt or sharp arrows, respectively. The α and β subunits of the TCR are indicated as open and solid boxes, respectively. The surrogate α chain of the pre-TCR is indicated as a hatched box.
FIG. 6
FIG. 6
Integrated view of the signaling defects observed in vav-deficient T cells. The biological process or signaling steps whose disruptions have been demonstrated experimentally are boxed. The role of PIP5-K in T cells is inferred from parallel studies with the B-cell CD19 receptor, but its role in T cells remains to be demonstrated experimentally. Possible new pathways predicted from the analysis of vav−/− lymphocytes are indicated by question marks. See the text for details.
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References

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