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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM081435-01A1
Application #
7382866
Study Section
Intercellular Interactions (ICI)
Program Officer
Deatherage, James F
Project Start
2007-09-28
Project End
2011-08-31
Budget Start
2007-09-28
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$658,976
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Jin, Dan; Durgan, Joanne; Hall, Alan (2015) Functional cross-talk between Cdc42 and two downstream targets, Par6B and PAK4. Biochem J 467:293-302
Durgan, Joanne; Tao, Guangbo; Walters, Matthew S et al. (2015) SOS1 and Ras regulate epithelial tight junction formation in the human airway through EMP1. EMBO Rep 16:87-96
Omelchenko, Tatiana; Rabadan, M Angeles; Hernández-Martínez, Rocío et al. (2014) ?-Pix directs collective migration of anterior visceral endoderm cells in the early mouse embryo. Genes Dev 28:2764-77
Xu, Xiaojian; Jin, Dan; Durgan, Joanne et al. (2013) LKB1 controls human bronchial epithelial morphogenesis through p114RhoGEF-dependent RhoA activation. Mol Cell Biol 33:2671-82
Omelchenko, Tatiana (2012) Regulation of collective cell migration by RhoGAP myosin IXA. Small GTPases 3:213-8
Omelchenko, Tatiana; Hall, Alan (2012) Myosin-IXA regulates collective epithelial cell migration by targeting RhoGAP activity to cell-cell junctions. Curr Biol 22:278-88
Magudia, Kirti; Lahoz, Aurelia; Hall, Alan (2012) K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc. J Cell Biol 198:185-94
Pulvirenti, Teodoro; Van Der Heijden, Maartje; Droms, Leif A et al. (2011) Dishevelled 2 signaling promotes self-renewal and tumorigenicity in human gliomas. Cancer Res 71:7280-90
Durgan, Joanne; Kaji, Noriko; Jin, Dan et al. (2011) Par6B and atypical PKC regulate mitotic spindle orientation during epithelial morphogenesis. J Biol Chem 286:12461-74
Wallace, Sean W; Magalhaes, Ana; Hall, Alan (2011) The Rho target PRK2 regulates apical junction formation in human bronchial epithelial cells. Mol Cell Biol 31:81-91

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