Role of Vav family proteins in cell signaling and cancer

Summary

Principal Investigator: XOSE BUSTELO
Abstract: The Vav family is a group of oncoproteins with three representatives in vertebrates (Vav, Vav2, and Vav3) and single members in invertebrates. These proteins catalyze the exchange of nucleotides on GTP-binding proteins of the Rho/Rac family, thereby facilitating the transition of these GTPases from their inactive (GDP-bound) to their active (GTP-bound) state. The enzyme activity of Vav proteins is tightly regulated during signal transduction by direct tyrosine phosphorylation. As a consequence, they only become activated when phosphorylated by upstream receptors with intrinsic or associated tyrosine kinase activity. Several lines of evidence demonstrate that the function of Vav proteins is crucial for both developmental and mitogenic processes. Thus, the deletion of vav and vav2 genes by homologous recombination results in defective maturation of lymphocyte lineages and lack of proper antigenic responses. Furthermore, the ectopic expression of gain-of-function mutants of Vav and Vav2 induces high levels of cellular transformation in rodent fibroblasts. Finally, recent results have implicated the Vav pathway in the pathogenic cycle of human lymphotropic viruses such as HIV, HTLV, and gamma-herpesviruses. The long-term objective of our laboratory is to achieve a comprehensive characterization of this protein family at the biochemical, structural, cellular, and organism level. To achieve this objective, the following studies will be carried out. In Aim 1, structural biology and biochemical techniques will be used to visualize the conformational changes underwent by these proteins upon binding to upstream regulators and GTPase substrates. In Aim 2, proteomic and expression cloning approaches will be used to reveal regulatory mechanisms of Vav proteins based on both posttranslational modifications and interactions with other intracellular molecules. In Aim 3, signaling techniques will be utilized to dissect new crosstalk and feedback mechanisms operating in the Vav pathway. In Aim 4, available knockout mice for the three vav family genes will be used to study the role of Vav proteins in cell signaling and physiological processes that, when deregulated, contribute to human disease. Taken together, these studies should provide a unified vision of the modus operandi of Vav proteins during signal transduction and, at the same time, supply valuable information for the design of pharmacological tools that could aid in the manipulation of Vav family-dependent biological processes in the future.
Funding Period: 1997-06-01 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc Rac-ing to the plasma membrane: the long and complex work commute of Rac1 during cell signaling
    Xose R Bustelo
    Centro de Investigacion del Cancer, Instituto de Biologia Molecular y Celular del Cancer, CSIC University of Salamanca, Campus Unamuno, Salamanca, Spain
    Small Gtpases 3:60-6. 2012
  2. pmc Vav3 is involved in GABAergic axon guidance events important for the proper function of brainstem neurons controlling cardiovascular, respiratory, and renal parameters
    Vincent Sauzeau
    Centro de Investigacion del Cancer, CSIC Salamanca University, Instituto de Neurociencias de Castilla y León and Departamento de Fisiología y Farmacología, Salamanca University, 37007 Salamanca, Spain
    Mol Biol Cell 21:4251-63. 2010
  3. pmc Conformational rearrangements upon Syk auto-phosphorylation
    Ernesto Arias-Palomo
    Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas CSIC, Ramiro de Maeztu, Madrid, Spain
    Biochim Biophys Acta 1794:1211-7. 2009
  4. pmc A transcriptional cross-talk between RhoA and c-Myc inhibits the RhoA/Rock-dependent cytoskeleton
    V Sauzeau
    Centro de Investigacion del Cancer, CSIC University of Salamanca, Campus Unamuno, Salamanca, Spain
    Oncogene 29:3781-92. 2010
  5. pmc Transcriptional factor aryl hydrocarbon receptor (Ahr) controls cardiovascular and respiratory functions by regulating the expression of the Vav3 proto-oncogene
    Vincent Sauzeau
    Centro de Investigacion del Cancer, Consejo Superior de Investigaciones Científicas Salamanca University, 37007 Salamanca, Spain
    J Biol Chem 286:2896-909. 2011
  6. pmc Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome
    Jelena Urosevic
    Molecular Oncology Program, Centro Nacional de Investigaciones Oncologicas CNIO, E 28029 Madrid, Spain
    Proc Natl Acad Sci U S A 108:5015-20. 2011
  7. pmc Coronin 1A promotes a cytoskeletal-based feedback loop that facilitates Rac1 translocation and activation
    Antonio Castro-Castro
    Centro de Investigacion del Cancer, CSIC Salamanca University, Campus Unamuno s n, Salamanca, Spain
    EMBO J 30:3913-27. 2011
  8. pmc Role of chimaerins, a group of Rac-specific GTPase activating proteins, in T-cell receptor signaling
    Maria Jose Caloca
    Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC University of Salamanca, Campus Unamuno, E 37007 Salamanca, Spain
    Cell Signal 20:758-70. 2008
  9. pmc The Gammaherpesvirus m2 protein manipulates the Fyn/Vav pathway through a multidocking mechanism of assembly
    Marta Pires de Miranda
    Instituto de Microbiologia e Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
    PLoS ONE 3:e1654. 2008
  10. pmc A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition
    Alberto J Schuhmacher
    Molecular Oncology Programme, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain
    J Clin Invest 118:2169-79. 2008

Scientific Experts

  • XOSE BUSTELO
  • Vincent Sauzeau
  • Sergio Ruiz
  • Ernesto Arias-Palomo
  • María J Montero
  • Maria A Sevilla
  • I M Berenjeno
  • Oscar Llorca
  • Antonio Castro-Castro
  • Jose M Carvajal-Gonzalez
  • Inmaculada M Berenjeno
  • Maria J Caloca
  • Marta Pires de Miranda
  • José R Couceiro
  • Lénia Rodrigues
  • Jelena Urosevic
  • Adelaida S Riolobos
  • V Sauzeau
  • Mariano Barbacid
  • Marta Canamero
  • Alberto J Schuhmacher
  • Maria Jose Caloca
  • Eugenio Santos
  • María A Recuero-Checa
  • Lorena Agudo-Ibáñez
  • J Pedro Simas
  • Jorge Pérez-Fernández
  • José L Zugaza
  • Jose M Lopez-Novoa
  • Rosario M Prieto-Sánchez
  • Daniela Poppe
  • Rubén A Bartolomé
  • R M Prieto-Sánchez
  • Joaquin Teixido
  • David García-Bernal
  • Angel C Román
  • Emma M Burkitt Wright
  • Pedro Fernandez-Salguero
  • Santiago Reig
  • María Barreira
  • Olivia Muriel
  • Virginia Ojeda
  • Inmaculada Navarro-Lérida
  • Miguel A Del Pozo
  • Felipe X Pimentel-Muiños
  • Mauricio Menacho-Marquez
  • Francisca Mulero
  • María L Soto-Montenegro
  • Manuel Desco
  • Antonio Abad
  • Sagrario Ortega
  • Dolores E López
  • Beatriz Rico
  • C Citterio
  • Gloria Fernandez
  • José A C Horta-Junior
  • Angel Carlos Roman
  • Sonia Mulero-Navarro
  • Pedro M Fernandez-Salguero
  • Jaime M Merino
  • Sofia Marques
  • Marta Alenquer
  • Filipa Lopes
  • Balbino Alarcon
  • Carmen Guerra
  • Pilar Delgado
  • Fernando Calvo
  • F Nunez
  • Mercedes Dosil
  • Angel Roman
  • Mirjana Jerkic
  • Javier De Las Rivas
  • Fatima Nuñez
  • Piero Crespo
  • Juan L Garcia
  • Brigitte Bartsch
  • Imke Tiede
  • Jesus M Hernandez
  • Jose A Hernandez
  • Markus F Neurath
  • Norma C Gutierrez
  • Juan V Rivas-Elena
  • Peter R Galle
  • Rafael Samaniego
  • Jesus San Miguel
  • Dennis Strand
  • Enrique de Alava
  • Paloma Sanchez-Mateos
  • Christoph Becker
  • Isabel Molina-Ortiz

Detail Information

Publications32

  1. pmc Rac-ing to the plasma membrane: the long and complex work commute of Rac1 during cell signaling
    Xose R Bustelo
    Centro de Investigacion del Cancer, Instituto de Biologia Molecular y Celular del Cancer, CSIC University of Salamanca, Campus Unamuno, Salamanca, Spain
    Small Gtpases 3:60-6. 2012
    ..This pathway is important for optimal Rac1 activation during the signaling of the EGF receptor, integrins, and the antigenic T-cell receptor...
  2. pmc Vav3 is involved in GABAergic axon guidance events important for the proper function of brainstem neurons controlling cardiovascular, respiratory, and renal parameters
    Vincent Sauzeau
    Centro de Investigacion del Cancer, CSIC Salamanca University, Instituto de Neurociencias de Castilla y León and Departamento de Fisiología y Farmacología, Salamanca University, 37007 Salamanca, Spain
    Mol Biol Cell 21:4251-63. 2010
    ..Our study discloses an essential and nonredundant role for this Vav family member in axon guidance events in brainstem neurons that control blood pressure and respiratory rates...
  3. pmc Conformational rearrangements upon Syk auto-phosphorylation
    Ernesto Arias-Palomo
    Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas CSIC, Ramiro de Maeztu, Madrid, Spain
    Biochim Biophys Acta 1794:1211-7. 2009
    ..These results suggest that the regulation of the activation of Syk might be modulated by subtle changes in the positioning of the regulatory domains rather than a full opening mechanism as proposed for the Src kinases...
  4. pmc A transcriptional cross-talk between RhoA and c-Myc inhibits the RhoA/Rock-dependent cytoskeleton
    V Sauzeau
    Centro de Investigacion del Cancer, CSIC University of Salamanca, Campus Unamuno, Salamanca, Spain
    Oncogene 29:3781-92. 2010
    ..These results reveal the presence of a hitherto unknown signaling feed-back loop between RhoA and c--Myc oncogenes that can contribute to maintain fluid cytoskeletal dynamics in cancer cells...
  5. pmc Transcriptional factor aryl hydrocarbon receptor (Ahr) controls cardiovascular and respiratory functions by regulating the expression of the Vav3 proto-oncogene
    Vincent Sauzeau
    Centro de Investigacion del Cancer, Consejo Superior de Investigaciones Científicas Salamanca University, 37007 Salamanca, Spain
    J Biol Chem 286:2896-909. 2011
    ..Our data also reveal the presence of sympathoexcitation and new cardiorespiratory defects in Ahr(-/-) mice...
  6. pmc Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome
    Jelena Urosevic
    Molecular Oncology Program, Centro Nacional de Investigaciones Oncologicas CNIO, E 28029 Madrid, Spain
    Proc Natl Acad Sci U S A 108:5015-20. 2011
    ..Moreover, they may serve as a tool to evaluate the potential therapeutic efficacy of B-RAF inhibitors and establish the precise window at which they could be effective against this congenital syndrome...
  7. pmc Coronin 1A promotes a cytoskeletal-based feedback loop that facilitates Rac1 translocation and activation
    Antonio Castro-Castro
    Centro de Investigacion del Cancer, CSIC Salamanca University, Campus Unamuno s n, Salamanca, Spain
    EMBO J 30:3913-27. 2011
    ..Genetic evidence demonstrates that this relay circuit is essential for generating sustained Rac1 activation levels during cell signalling...
  8. pmc Role of chimaerins, a group of Rac-specific GTPase activating proteins, in T-cell receptor signaling
    Maria Jose Caloca
    Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC University of Salamanca, Campus Unamuno, E 37007 Salamanca, Spain
    Cell Signal 20:758-70. 2008
    ..Taken together, these results identify chimaerins as candidates for the downmodulation of Rac1 in T-lymphocytes and, in addition, uncover a novel regulatory mechanism that mediates their activation in T-cells...
  9. pmc The Gammaherpesvirus m2 protein manipulates the Fyn/Vav pathway through a multidocking mechanism of assembly
    Marta Pires de Miranda
    Instituto de Microbiologia e Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
    PLoS ONE 3:e1654. 2008
    ..Taken together, these results indicate that the M2 phosphotyrosine motif and the previously described M2 proline rich region work in a concerted manner to manipulate the signaling machinery of the host B-cell...
  10. pmc A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition
    Alberto J Schuhmacher
    Molecular Oncology Programme, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain
    J Clin Invest 118:2169-79. 2008
    ..In addition, it partially alleviated the observed cardiomyopathies. These mice should help in elucidating the etiology of CS symptoms, identifying additional defects, and evaluating potential therapeutic strategies...
  11. pmc Mechanistic analysis of the amplification and diversification events induced by Vav proteins in B-lymphocytes
    Maria J Caloca
    Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Cientificas, University of Salamanca, Campus Unamuno, Salamanca E 37007, Spain
    J Biol Chem 283:36454-64. 2008
    ..Finally, we show that the oncogenic versions of Vav1 and RhoA can activate alternative routes that could contribute to signal amplification and diversification events in transformed lymphocytes...
  12. pmc Identification of the Rock-dependent transcriptome in rodent fibroblasts
    Inmaculada M Berenjeno
    Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer IBMCC, CSIC University of Salamanca, Campus Unamuno, Salamanca, Spain
    Clin Transl Oncol 10:726-38. 2008
    ..In addition, they suggest that the main target of these serine/threonine kinases is the phosphoproteome and not the transcriptome...
  13. pmc The dioxin receptor regulates the constitutive expression of the vav3 proto-oncogene and modulates cell shape and adhesion
    Jose M Carvajal-Gonzalez
    Departamento de Bioquimica y Biologia Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain
    Mol Biol Cell 20:1715-27. 2009
    ..By modulating Vav3-dependent signaling, AhR could regulate cell shape, adhesion, and migration under physiological conditions and, perhaps, in certain pathological states...
  14. pmc The use of knockout mice reveals a synergistic role of the Vav1 and Rasgrf2 gene deficiencies in lymphomagenesis and metastasis
    Sergio Ruiz
    Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas University of Salamanca, Salamanca, Spain
    PLoS ONE 4:e8229. 2009
    ..Vav1 and RasGRF2 are GDP/GTP exchange factors for Ras superfamily GTPases with roles in the development and/or effector functions of T-lymphocytes...
  15. pmc The Rho/Rac exchange factor Vav2 controls nitric oxide-dependent responses in mouse vascular smooth muscle cells
    Vincent Sauzeau
    Centro de Investigacion del Cancer, Instituto de Biologia Molecular y Celular del Cancer, CSIC University of Salamanca, Campus Unamuno, Salamanca, Spain
    J Clin Invest 120:315-30. 2010
    ....
  16. ncbi CD147 inhibits the nuclear factor of activated T-cells by impairing Vav1 and Rac1 downstream signaling
    Sergio Ruiz
    Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas University of Salamanca, Campus Unamuno, E 37007 Salamanca, Spain
    J Biol Chem 283:5554-66. 2008
    ..Taken together, these results indicate that CD147, via the selective inhibition of specific downstream elements of the Vav1/Rac1 route, contributes to the negative regulation of T-cell responses...
  17. pmc 3D structure of Syk kinase determined by single-particle electron microscopy
    Ernesto Arias-Palomo
    Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Científicas Spanish National Research Council, CSIC, Ramiro de Maeztu, 9, E28040 Madrid, Spain
    Biochim Biophys Acta 1774:1493-9. 2007
    ..Such configuration suggests an inhibition of the N-terminal domains on its catalytic activity. The phosphotyrosine binding pockets of both SH2 domains are not occluded and they could interact with other phosphoproteins...
  18. pmc Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin alpha4beta1
    David García-Bernal
    Department of Immunology, Centro de Investigaciones Biologicas, CSIC, 28006 Madrid, Spain
    Mol Biol Cell 16:3223-35. 2005
    ..These results indicate that activation of Vav1-Rac signaling pathway by CXCL12 represents an important inside-out event controlling efficient up-regulation of alpha4beta1-dependent T lymphocyte adhesion...
  19. pmc Phylogenetic conservation of the regulatory and functional properties of the Vav oncoprotein family
    José R Couceiro
    Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC University of Salamanca, Campus Unamuno, E 37007 Salamanca, Spain
    Exp Cell Res 308:364-80. 2005
    ..Moreover, they indicate that the foundations for the regulatory and enzymatic activities of this protein family have been set up very early during evolution...
  20. pmc Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins
    Daniela Poppe
    Laboratory of Immunology, I Department of Medicine, University of Mainz, Mainz, Germany
    J Immunol 176:640-51. 2006
    ..These findings provide novel insights into the immunosuppressive effects of azathioprine and suggest that antagonists of the Vav-Rac signaling pathway may be useful for suppression of T cell-dependent pathogenic immune responses...
  21. pmc Activation of Vav/Rho GTPase signaling by CXCL12 controls membrane-type matrix metalloproteinase-dependent melanoma cell invasion
    Rubén A Bartolomé
    Department of Immunology, Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain
    Cancer Res 66:248-58. 2006
    ..Together, these data indicate that activation of Jak/Vav/Rho GTPase pathway by CXCL12 is a key signaling event for MT1-MMP/MMP-2-dependent melanoma cell invasion...
  22. pmc Involvement of the Rho/Rac family member RhoG in caveolar endocytosis
    R M Prieto-Sánchez
    Centro de Investigacion del Cancer, Instituto de Biología Molecular y Celular del Cáncer IBMCC, and Red Temática Cooperativa de Centros de Cáncer, CSIC University of Salamanca, Spain
    Oncogene 25:2961-73. 2006
    ..Taken together, these observations assign a novel function to RhoG and suggest that caveolar trafficking, as previously shown for other endocytic routes, is modulated by GTPases of the Ras superfamily...
  23. pmc Overexpression of the VAV proto-oncogene product is associated with B-cell chronic lymphocytic leukaemia displaying loss on 13q
    Rosario M Prieto-Sánchez
    Centro de Investigacion del Cancer, Hospital Clinico Universitario de Salamanca, Salamanca, Spain
    Br J Haematol 133:642-5. 2006
    ..4%) versus other B-CLLs (23.4%, P = 0.001). Overexpression of VAV protein is a frequent event in patients with B-CLL displaying loss of 13q sequences...
  24. pmc Activation of Vav by the gammaherpesvirus M2 protein contributes to the establishment of viral latency in B lymphocytes
    Lénia Rodrigues
    Instituto Gulbenkian de Ciencia, Oeias, Portugal
    J Virol 80:6123-35. 2006
    ..These results reveal a novel strategy used by the murine gammaherpesvirus family to subvert the lymphocyte signaling machinery to its own benefit...
  25. pmc Vav3 proto-oncogene deficiency leads to sympathetic hyperactivity and cardiovascular dysfunction
    Vincent Sauzeau
    Centro de Investigacion del Cancer, University of Salamanca, Campus Unamuno, E 37007 Salamanca, Spain
    Nat Med 12:841-5. 2006
    ....
  26. pmc Loss of Vav2 proto-oncogene causes tachycardia and cardiovascular disease in mice
    Vincent Sauzeau
    Centro de Investigacion del Cancer, Instituto de Biologia Molecular y Celular del Cancer, University of Salamanca, E 37007 Salamanca, Spain
    Mol Biol Cell 18:943-52. 2007
    ..Together, these results indicate that Vav2 plays crucial roles in the maintenance of cardiovascular homeostasis in mice...
  27. pmc Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases
    I M Berenjeno
    Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer IBMCC, CSIC University of Salamanca, Campus Unamuno, Salamanca, Spain
    Oncogene 26:4295-305. 2007
    ..These results reveal the complexity of the genetic program orchestrated by the Rho subfamily and pinpoint protein networks that mediate different aspects of the malignant phenotype of Rho-transformed cells...
  28. pmc GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo
    Xose R Bustelo
    Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer IBMCC, CSIC University of Salamanca, Salamanca, Spain
    Bioessays 29:356-70. 2007
    ..In this review, we will provide an overview on the recent advances in this field regarding the mechanism of regulation and signaling, and the roles in vivo of this important GTPase family...
  29. pmc The 90S preribosome is a multimodular structure that is assembled through a hierarchical mechanism
    Jorge Pérez-Fernández
    Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC University of Salamanca, Campus Unamuno, E 37007 Salamanca, Spain
    Mol Cell Biol 27:5414-29. 2007
    ..Together, our data identify the mechanism of assembly of the 90S preribosome and offer novel information about its internal architecture...
  30. pmc Transcriptomal profiling of site-specific Ras signals
    Lorena Agudo-Ibáñez
    Instituto de Investigaciones Biomedicas, Consejo Superior de Investigaciones Cientificas CSIC, Departamento de Biologia Molecular, Unidad de Biomedicina, CSIC Universidad de Cantabria, Santander, Spain
    Cell Signal 19:2264-76. 2007
    ..Overall, this report reveals the complexity and variability of the different genetic programs orchestrated by Ras from its main sublocalizations...
  31. pmc RasGRF2, a guanosine nucleotide exchange factor for Ras GTPases, participates in T-cell signaling responses
    Sergio Ruiz
    Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC University of Salamanca, Campus Unamuno, E 37007 Salamanca, Spain
    Mol Cell Biol 27:8127-42. 2007
    ..These results identify RasGRF2 as an additional component of the signaling machinery involved in T-cell receptor- and NF-AT-mediated immune responses...
  32. pmc Global conformational rearrangements during the activation of the GDP/GTP exchange factor Vav3
    Oscar Llorca
    Centro de Investigaciones Biologicas, CSIC, Madrid, Spain
    EMBO J 24:1330-40. 2005
    ....