Rho GTPase and polarity signaling pathways in morphogenesis and migration

Summary

Principal Investigator: Alan Hall
Affiliation: Memorial Sloan-Kettering Cancer Center
Country: USA
Abstract: The signal transduction pathways driving morphogenesis and migration are not well understood, yet defects in these processes underlie a wide spectrum of human diseases and syndromes, including mental retardation, Wiskott-Aldrich syndrome, faciogenital dysplasia, hearing loss and cancer. The long term objectives of this proposal are to delineate the cellular mechanisms that control morphogenesis and migration. The approaches used here involve: (i) disrupting cell-cell contacts in tissue culture monolayers to induce polarized migration and (ii) promoting cell-cell contact between epithelial cells to induce polarized morphogenesis. The key hypothesis is that despite being very different biological processes, morphogenesis and migration share many of the same molecular components and signaling pathways and that Rho GTPases play a central role in both. Disrupting cell-cell contacts in fibroblast monolayers to induce migration activates Rho GTPase- dependent signal transduction pathways that lead to polarization of the actin and microtubule cytoskeletons along an anterior/posterior axis. Preliminary work has shown that Wnt5a and the intracellular adaptor protein disheveled are also required for polarization of both cytoskeletal networks and in Aim I, the biochemical relationship between Rho GTPases and Wnt pathways will be determined. In Aim II, the Rho GTPase pathways regulating apical-basal polarity during morphogenesis and anterior-posterior polarity during migration will be identified in epithelial cells. The spatially localized activation and responses of Rho GTPases are mediated by a family of 82 guanine nucleotide exchange factors (GEFs), 67 GTPase activating proteins (GAPs) and some 100 target proteins. The GEFs, GAPs and targets involved in controlling epithelial cell migration and morphogenesis will be identified. This program of research will lead to a significant advance in understanding the control of migration and morphogenesis and provide a basis for new therapeutic opportunities in a wide range of human disorders.Public Health Relevance: In the embryo, cells must migrate to appropriate locations and adopt specialized shapes to form organized tissues and organs. These structures then need to be maintained throughout adult life. The biochemical mechanisms controlling these processes are poorly understood, but defects contribute to a wide range of congenital and acquired human disorders, ranging from mental retardation to cancer.
Funding Period: 2007-09-28 - 2011-08-31
more information: NIH RePORT

Top Publications

  1. pmc LKB1 controls human bronchial epithelial morphogenesis through p114RhoGEF-dependent RhoA activation
    Xiaojian Xu
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    Mol Cell Biol 33:2671-82. 2013
  2. pmc K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc
    Kirti Magudia
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    J Cell Biol 198:185-94. 2012
  3. pmc Regulation of collective cell migration by RhoGAP myosin IXA
    Tatiana Omelchenko
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
    Small Gtpases 3:213-8. 2012
  4. pmc Myosin-IXA regulates collective epithelial cell migration by targeting RhoGAP activity to cell-cell junctions
    Tatiana Omelchenko
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Curr Biol 22:278-88. 2012
  5. pmc Dishevelled 2 signaling promotes self-renewal and tumorigenicity in human gliomas
    Teodoro Pulvirenti
    Cell Biology Program, Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York 10021, USA
    Cancer Res 71:7280-90. 2011
  6. pmc Par6B and atypical PKC regulate mitotic spindle orientation during epithelial morphogenesis
    Joanne Durgan
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    J Biol Chem 286:12461-74. 2011
  7. pmc The Rho target PRK2 regulates apical junction formation in human bronchial epithelial cells
    Sean W Wallace
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, 1274 York Ave, New York, NY 10065, USA
    Mol Cell Biol 31:81-91. 2011
  8. pmc LKB1 tumor suppressor protein regulates actin filament assembly through Rho and its exchange factor Dbl independently of kinase activity
    Xiaojian Xu
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
    BMC Cell Biol 11:77. 2010
  9. pmc Cellular responses to extracellular guidance cues
    ANASTACIA BERZAT
    Memorial Sloan Kettering Cancer Center, Cell Biology Program, New York, NY 10065, USA
    EMBO J 29:2734-45. 2010
  10. pmc Rac1-dependent collective cell migration is required for specification of the anterior-posterior body axis of the mouse
    Isabelle Migeotte
    Developmental Biology Program, Sloan Kettering Institute, New York, New York, United States of America
    PLoS Biol 8:e1000442. 2010

Scientific Experts

Detail Information

Publications12

  1. pmc LKB1 controls human bronchial epithelial morphogenesis through p114RhoGEF-dependent RhoA activation
    Xiaojian Xu
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    Mol Cell Biol 33:2671-82. 2013
    ..Together, LKB1 and p114RhoGEF control RhoA activity in these cells to promote apical junction assembly. ..
  2. pmc K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc
    Kirti Magudia
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    J Cell Biol 198:185-94. 2012
    ..We conclude that ERK-mediated up-regulation of c-myc by K-Ras or B-Raf oncogenes disrupts the establishment of apical/basolateral polarity in colon epithelial cells independently of its effect on proliferation...
  3. pmc Regulation of collective cell migration by RhoGAP myosin IXA
    Tatiana Omelchenko
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
    Small Gtpases 3:213-8. 2012
    ..Here, I discuss how myosin IXA regulates Rho and the actin cytoskeleton during the assembly of nascent cell-cell contacts and how this might contribute to collective epithelial migration...
  4. pmc Myosin-IXA regulates collective epithelial cell migration by targeting RhoGAP activity to cell-cell junctions
    Tatiana Omelchenko
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Curr Biol 22:278-88. 2012
    ....
  5. pmc Dishevelled 2 signaling promotes self-renewal and tumorigenicity in human gliomas
    Teodoro Pulvirenti
    Cell Biology Program, Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York 10021, USA
    Cancer Res 71:7280-90. 2011
    ..The data therefore suggest that both canonical and noncanonical Wnt signaling pathways downstream of Dvl2 cooperate to maintain the proliferative capacity of human glioblastomas...
  6. pmc Par6B and atypical PKC regulate mitotic spindle orientation during epithelial morphogenesis
    Joanne Durgan
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    J Biol Chem 286:12461-74. 2011
    ..We conclude that Par6B and aPKC control mitotic spindle orientation in polarized epithelia and, furthermore, that aPKC coordinately regulates multiple processes to promote morphogenesis...
  7. pmc The Rho target PRK2 regulates apical junction formation in human bronchial epithelial cells
    Sean W Wallace
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, 1274 York Ave, New York, NY 10065, USA
    Mol Cell Biol 31:81-91. 2011
    ..We conclude that PRK2 is recruited to nascent cell-cell contacts through its C2-like and Rho-binding domains and promotes junctional maturation through a kinase-dependent pathway...
  8. pmc LKB1 tumor suppressor protein regulates actin filament assembly through Rho and its exchange factor Dbl independently of kinase activity
    Xiaojian Xu
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
    BMC Cell Biol 11:77. 2010
    ..In addition, LKB1 is homologous to PAR-4, a polarity protein first described in C. elegans, while activation of LKB1 in mammalian epithelial cells induces the polarized assembly of actin filaments...
  9. pmc Cellular responses to extracellular guidance cues
    ANASTACIA BERZAT
    Memorial Sloan Kettering Cancer Center, Cell Biology Program, New York, NY 10065, USA
    EMBO J 29:2734-45. 2010
    ....
  10. pmc Rac1-dependent collective cell migration is required for specification of the anterior-posterior body axis of the mouse
    Isabelle Migeotte
    Developmental Biology Program, Sloan Kettering Institute, New York, New York, United States of America
    PLoS Biol 8:e1000442. 2010
    ..The data show that Rac1-mediated epithelial migration of the AVE is a crucial step in the establishment of the mammalian body plan and suggest that Rac1 is essential for collective migration in mammalian tissues...
  11. pmc Cdc42 regulates apical junction formation in human bronchial epithelial cells through PAK4 and Par6B
    Sean W Wallace
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Mol Biol Cell 21:2996-3006. 2010
    ..This study demonstrates that controlled regulation of PAK4 is required for apical junction formation in lung epithelial cells and highlights potential cross-talk between two Cdc42 targets, PAK4 and Par6B...
  12. pmc Cdc42 controls spindle orientation to position the apical surface during epithelial morphogenesis
    Aron B Jaffe
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    J Cell Biol 183:625-33. 2008
    ..We conclude that Cdc42 regulates epithelial tissue morphogenesis by controlling spindle orientation during cell division...