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Host deficiency in Vav2/3 guanine nucleotide exchange factors impairs tumor growth, survival, and angiogenesis in vivo.
Brantley-Sieders DM, Zhuang G, Vaught D, Freeman T, Hwang Y, Hicks D, Chen J
(2009) Mol Cancer Res 7: 615-23
MeSH Terms: Animals, Carcinoma, Lewis Lung, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Survival, Coculture Techniques, Endothelial Cells, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Neoplasms, Experimental, Neovascularization, Pathologic, Proto-Oncogene Proteins c-vav, Transplantation, Homologous, Tumor Burden, von Willebrand Factor
Show Abstract · Added May 23, 2013
Vav guanine nucleotide exchange factors modulate changes in cytoskeletal organization through activation of Rho, Rac, and Cdc42 small GTPases. Although Vav1 expression is restricted to the immune system, Vav2 and Vav3 are expressed in several tissues, including highly vascularized organs. Here, we provide the first evidence that Vav2 and Vav3 function within the tumor microenvironment to promote tumor growth, survival, and neovascularization. Host Vav2/3 deficiency reduced microvascular density, as well as tumor growth and/or survival, in transplanted B16 melanoma and Lewis lung carcinoma models in vivo. These defects were due in part to Vav2/3 deficiency in endothelial cells. Vav2/3-deficient endothelial cells displayed reduced migration in response to tumor cells in coculture migration assays, and failed to incorporate into tumor vessels and enhance tumor volume in tumor-endothelial cotransplantation experiments. These data suggest that Vav2/3 guanine nucleotide exchange factors play a critical role in host-mediated tumor progression and angiogenesis, particularly in tumor endothelium.
1 Communities
2 Members
0 Resources
19 MeSH Terms
Identification and functional analysis of phosphorylated tyrosine residues within EphA2 receptor tyrosine kinase.
Fang WB, Brantley-Sieders DM, Hwang Y, Ham AJ, Chen J
(2008) J Biol Chem 283: 16017-26
MeSH Terms: Amino Acid Substitution, Animals, Cell Movement, Endothelial Cells, Ephrin-A1, Guanine Nucleotide Exchange Factors, Mice, Mice, Transgenic, Mutation, Missense, Neoplasm Invasiveness, Neovascularization, Pathologic, Neuropeptides, Peptide Mapping, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-vav, Receptor, EphA2, Signal Transduction, Tyrosine, rac GTP-Binding Proteins, rac1 GTP-Binding Protein
Show Abstract · Added March 5, 2014
EphA2 is a member of the Eph family of receptor tyrosine kinases. EphA2 mediates cell-cell communication and plays critical roles in a number of physiological and pathologic responses. We have previously shown that EphA2 is a key regulator of tumor angiogenesis and that tyrosine phosphorylation regulates EphA2 signaling. To understand the role of EphA2 phosphorylation, we have mapped phosphorylated tyrosines within the intracellular region of EphA2 by a combination of mass spectrometry analysis and phosphopeptide mapping using two-dimensional chromatography in conjunction with site-directed mutagenesis. The function of these phosphorylated tyrosine residues was assessed by mutational analysis using EphA2-null endothelial cells reconstituted with EphA2 tyrosine-to-phenylalanine or tyrosine-to-glutamic acid substitution mutants. Phosphorylated Tyr(587) and Tyr(593) bind to Vav2 and Vav3 guanine nucleotide exchange factors, whereas Tyr(P)(734) binds to the p85 regulatory subunit of phosphatidylinositol 3-kinase. Mutations that uncouple EphA2 with Vav guanine nucleotide exchange factors or p85 are defective in Rac1 activation and cell migration. Finally, EphA2 mutations in the juxtamembrane region (Y587F, Y593F, Y587E/Y593E), kinase domain (Y734F), or SAM domain (Y929F) inhibited ephrin-A1-induced vascular assembly. In addition, EphA2-null endothelial cells reconstituted with these mutants were unable to incorporate into tumor vasculature, suggesting a critical role of these phosphorylation tyrosine residues in transducing EphA2 signaling in vascular endothelial cells during tumor angiogenesis.
1 Communities
1 Members
0 Resources
23 MeSH Terms
Integrin alpha1beta1 controls reactive oxygen species synthesis by negatively regulating epidermal growth factor receptor-mediated Rac activation.
Chen X, Abair TD, Ibanez MR, Su Y, Frey MR, Dise RS, Polk DB, Singh AB, Harris RC, Zent R, Pozzi A
(2007) Mol Cell Biol 27: 3313-26
MeSH Terms: Animals, Cell Membrane, Cell Shape, Cells, Cultured, Collagen, Down-Regulation, Enzyme Activation, ErbB Receptors, Humans, Integrin alpha1beta1, Ligands, Mesangial Cells, Mice, Mice, Knockout, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-vav, Reactive Oxygen Species, Receptors, Collagen, rac GTP-Binding Proteins
Show Abstract · Added February 24, 2014
Integrins control many cell functions, including generation of reactive oxygen species (ROS) and regulation of collagen synthesis. Mesangial cells, found in the glomerulus of the kidney, are able to produce large amounts of ROS via the NADPH oxidase. We previously demonstrated that integrin alpha1-null mice develop worse fibrosis than wild-type mice following glomerular injury and this is due, in part, to excessive ROS production by alpha1-null mesangial cells. In the present studies, we describe the mechanism whereby integrin alpha1-null mesangial cells produce excessive ROS. Integrin alpha1-null mesangial cells have constitutively increased basal levels of activated Rac1, which result in its increased translocation to the cell membrane, excessive ROS production, and consequent collagen IV deposition. Basal Rac1 activation is a direct consequence of ligand-independent increased epidermal growth factor receptor (EGFR) phosphorylation in alpha1-null mesangial cells. Thus, our study demonstrates that integrin alpha1beta1-EGFR cross talk is a key step in negatively regulating Rac1 activation, ROS production, and excessive collagen synthesis, which is a hallmark of diseases characterized by irreversible fibrosis.
1 Communities
4 Members
0 Resources
20 MeSH Terms
HER2/Neu (ErbB2) signaling to Rac1-Pak1 is temporally and spatially modulated by transforming growth factor beta.
Wang SE, Shin I, Wu FY, Friedman DB, Arteaga CL
(2006) Cancer Res 66: 9591-600
MeSH Terms: Actinin, Actins, Adenocarcinoma, Animals, Breast Neoplasms, Cell Line, Tumor, Female, Humans, Mammary Neoplasms, Experimental, Mice, Mice, Transgenic, Neoplasm Metastasis, Neuropeptides, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-vav, Pseudopodia, Receptor, ErbB-2, Recombinant Fusion Proteins, Signal Transduction, Transforming Growth Factor beta1, p21-Activated Kinases, rac GTP-Binding Proteins, rac1 GTP-Binding Protein
Show Abstract · Added March 5, 2014
In HER2 (ErbB2)-overexpressing cells, transforming growth factor beta (TGF-beta), via activation of phosphoinositide-3 kinase (PI3K), recruits actin and actinin to HER2, which then colocalizes with Vav2, activated Rac1, and Pak1 at cell protrusions. This results in prolonged Rac1 activation, enhanced motility and invasiveness, Bad phosphorylation, uncoupling of Bad/Bcl-2, and enhanced cell survival. The recruitment of the HER2/Vav2/Rac1/Pak1/actin/actinin complex to lamellipodia was abrogated by actinin siRNAs, dominant-negative (dn) p85, gefitinib, and dn-Rac1 or dn-Pak1, suggesting that the reciprocal interplay of PI3K, HER2 kinase, and Rac GTPases with the actin cytoskeleton is necessary for TGF-beta action in oncogene-overexpressing cells. Thus, by recruiting the actin skeleton, TGF-beta "cross-links" this signaling complex at cell lamellipodia; this prolongs Rac1 activation and increases metastatic properties and survival of HER2-overexpressing cells.
0 Communities
1 Members
0 Resources
25 MeSH Terms
Essential role of Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis.
Hunter SG, Zhuang G, Brantley-Sieders D, Swat W, Cowan CW, Chen J
(2006) Mol Cell Biol 26: 4830-42
MeSH Terms: Animals, Cell Movement, Cytoskeleton, Endothelial Cells, Enzyme Activation, Ephrin-A1, Guanine Nucleotide Exchange Factors, Mice, Mice, Mutant Strains, Neovascularization, Physiologic, Protein Interaction Mapping, Protein Structure, Tertiary, Proto-Oncogene Proteins c-vav, Receptor, EphA2, rac1 GTP-Binding Protein
Show Abstract · Added March 5, 2014
Angiogenesis, the process by which new blood vessels are formed from preexisting vasculature, is critical for vascular remodeling during development and contributes to the pathogenesis of diseases such as cancer. Prior studies from our laboratory demonstrate that the EphA2 receptor tyrosine kinase is a key regulator of angiogenesis in vivo. The EphA receptor-mediated angiogenic response is dependent on activation of Rho family GTPase Rac1 and is regulated by phosphatidylinositol 3-kinase. Here we report the identification of Vav2 and Vav3 as guanine nucleotide exchange factors (GEFs) that link the EphA2 receptor to Rho family GTPase activation and angiogenesis. Ephrin-A1 stimulation recruits the binding of Vav proteins to the activated EphA2 receptor. The induced association of EphA receptor and Vav proteins modulates the activity of Vav GEFs, leading to activation of Rac1 GTPase. Overexpression of either Vav2 or Vav3 in primary microvascular endothelial cells promotes Rac1 activation, cell migration, and assembly in response to ephrin-A1 stimulation. Conversely, loss of Vav2 and Vav3 GEFs inhibits Rac1 activation and ephrin-A1-induced angiogenic responses both in vitro and in vivo. In addition, embryonic fibroblasts derived from Vav2-/- Vav3-/- mice fail to spread on an ephrin-A1-coated surface and exhibit a significant decrease in the formation of ephrin-A1-induced lamellipodia and filopodia. These findings suggest that Vav GEFs serve as a molecular link between EphA2 receptors and the actin cytoskeleton and provide an important mechanism for EphA2-mediated angiogenesis.
1 Communities
1 Members
0 Resources
15 MeSH Terms
Activation and association of the Tec tyrosine kinase with the human prolactin receptor: mapping of a Tec/Vav1-receptor binding site.
Kline JB, Moore DJ, Clevenger CV
(2001) Mol Endocrinol 15: 832-41
MeSH Terms: 3T3 Cells, Animals, Binding Sites, COS Cells, Cell Cycle Proteins, Enzyme Activation, Female, Humans, Ligands, Mice, Peptide Mapping, Phosphorylation, Precipitin Tests, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-vav, Receptors, Prolactin, Recombinant Proteins, Transfection, rac1 GTP-Binding Protein
Show Abstract · Added October 24, 2013
Stimulation of the PRL receptor (PRLr) results in the activation of the guanine nucleotide exchange factor (GEF) p95Vav1 with corresponding alterations in cytoarchitecture and cell motility. To better understand the mechanisms involved in the regulation of Vav1 activity, the role of the tyrosine kinase p70Tec was examined. Coimmunoprecipitation and in vitro kinase assays revealed that ligand stimulation of the PRLr resulted in the rapid activation of Tec and its concomitant association with the PRLR: When coexpressed in COS-1 cells, both Vav1 and Tec were found to associate with the PRLr in the presence of ligand. In the absence of receptor, a constitutive complex between Vav1 and Tec was noted. Both Vav1 and Tec, however, were capable of independent engagement of a bipartite intracellular domain of the PRLR: Deletion mapping studies confined this interaction to residues 323 to 527 of the intracellular domain of the PRLR: Furthermore, Tec enhanced the GEF activity of Vav1 as evidenced by an increase in GTP-bound Rac1. These data would suggest a pivotal function for the formation of a Tec/Vav1/PRLr complex during PRL-driven signal transduction, given the role of Vav1 in the control of cell proliferation and the regulation of Rho family-mediated cytoskeletal alterations.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Systematic analysis of the role of CD19 cytoplasmic tyrosines in enhancement of activation in Daudi human B cells: clustering of phospholipase C and Vav and of Grb2 and Sos with different CD19 tyrosines.
Brooks SR, Li X, Volanakis EJ, Carter RH
(2000) J Immunol 164: 3123-31
MeSH Terms: Adaptor Proteins, Signal Transducing, Adjuvants, Immunologic, Antigens, CD19, B-Lymphocytes, Calcium Signaling, Cell Cycle Proteins, Cytoplasm, Exons, GRB2 Adaptor Protein, Humans, Isoenzymes, Lymphocyte Activation, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Molecular Weight, Mutagenesis, Site-Directed, Peptide Mapping, Phospholipase C gamma, Phosphopeptides, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-vav, Receptors, Antigen, B-Cell, Son of Sevenless Protein, Drosophila, Tumor Cells, Cultured, Type C Phospholipases, Tyrosine, Vanadates
Show Abstract · Added May 27, 2014
CD19 is a coreceptor on B cells that enhances the increase in cytoplasmic calcium and ERK2 activation when coligated with the B cell Ag receptor. Constructs containing point mutations and truncations were expressed in Daudi human B lymphoblastoid cells to systematically determine the requirement for individual CD19 cytoplasmic tyrosines in these responses. Evidence for activity was found for Y330, Y360, and Y421 as well as that previously published for Y391. Precipitates formed with phosphopeptides consisting of CD19 sequences flanking these residues were used to screen for cytoplasmic proteins that mediate signaling. Phosphopeptide Y330 precipitated Grb2 and Sos, whereas phosphopeptides Y391 and Y421 both precipitated Vav and phospholipase C-gamma2. These molecules also were found associated with native CD19. In mapping studies with altered constructs, CD19 Y330 and/or Y360 were necessary for binding Grb2 and Sos. Vav associated with CD19 constitutively in unstimulated cells by a tyrosine-independent mechanism requiring the portion of CD19 encoded by exons 9-12. After B cell Ag receptor stimulation, Vav association was tyrosine-dependent, but binding was influenced by multiple residues. However, when maximally phosphorylated by pervanadate, Y391 and, to a lesser extent, Y421 were sufficient. CD19 Y391 was also both necessary and sufficient for binding phospholipase C-gamma2. Thus, different tyrosines along the CD19 cytoplasmic domain provide scaffolding for the formation of complexes of different signaling molecules.
0 Communities
1 Members
0 Resources
28 MeSH Terms