Our Faculty > Barry M. Gumbiner

Barry M. Gumbiner

Barry M. Gumbiner

Education

  • PhD, University of California, San Francisco, CA
  • Postdoc, MIT, Cambridge, MA
  • Postdoc, EMBL, Heidelberg, West Germany
  • BS, University of Cincinnati, Cincinnati, Ohio

Primary Appointment

  • Professor, Cell Biology

Contact

Research Interest(s)

Cell Adhesion and Morphogenesis; Wnt Signaling; Cadherins and Catenins; Development and Cancer

Research Description

Cadherin and beta-catenin signaling in development and cancer
We are studying how beta-catenin functions in its two key roles; in cell adhesion as a binding protein for cadherin cell adhesion molecules, and in the Wnt signaling pathway as a binding partner for the TCF transcription factor. E-cadherin acts as a tumor suppressor protein by inhibiting the Wnt stimulated TCF-dependent signaling activity of beta-catenin. In this way E-cadherin slows the proliferation of colorectal tumor cells. In other types of tumors, such as breast and prostate, E-cadherin acts to suppress tumor cell invasion, but in these cases invasion suppression involves alternate beta-catenin-dependent signaling pathways distinct from the canonical Wnt/beta-catenin/TCF signaling pathway. Furthermore, E-cadherin and beta-catenin directly mediate the contact inhibition of growth in a number of cell types; again by an alternate beta-catenin-dependent pathway. Current efforts are directed at elucidating the alternate molecular pathways by which beta-catenin mediates these growth and tumor suppressor functions of E-cadherin. We have also discovered that beta-catenin occurs in several distinct molecular forms which regulate its targeting to either TCF transcriptional complexes in the nucleus or cadherin adhesive complexes at the plasma membrane; Wnt signaling generates a TCF-selective form. Beta-catenin targeting and degradation is regulated by a cytoplasmic protein complex that includes the APC tumor suppressor protein, axin, and GSK3b, and we are investigating the mechanisms by which these proteins function in beta-catenin targeting and Wnt signaling.


Regulation of cadherin-mediated adhesion during tissue morphogenesis
Cadherins play important roles in morphogenetic processes that shape tissues in embryos and in growing adult organs. Tissue morphogenesis involves cell movements and cell rearrangements, processes that require a continual controlled breaking and re-making of adhesive bonds. We are studying how the regulation of cadherin adhesive function drives tissue morphogenesis during gastrulation of the Xenopus embryo. Regulation of a Xenopus C-cadherin in response to TGFb type growth factors is required for the elongation of tissues that drives the formation of the body axis. C-cadherin is also regulated spatially by the expression of a protocadherin (a poorly understood subfamily of cadherin proteins) call PAPC (paraxial protocadherin). We are now investigating the molecular mechanisms underlying the regulation of C-cadherin adhesion by TGFb factors and PAPC. These studies deal with a range of interesting problems, including the analysis of the basic molecular mechanism of cadherin adhesive binding, the molecular basis of PAPC function, the functions of the catenins in controlling cadherins, and the mechanism by which signaling pathways regulate these functions dynamically in the cell. At the level of tissue development, we are trying to understand how the temporal and spatial regulation of cadherin-mediated cell adhesion controls the cell movements and cell rearrangements that drive morphogenesis.


Selected Publications

  • Mahadevaiyer S, Xu C, Gumbiner B. Characterization of a 60S complex of the adenomatous polyposis coli tumor suppressor protein. Biochimica et biophysica acta. 2006;1773(2): 120-30. PMID: 17126424 | PMCID: PMC1808328
  • Chen X, Gumbiner B. Crosstalk between different adhesion molecules. Current opinion in cell biology. 2006;18(5): 572-8. PMID: 16859906
  • Chen X, Gumbiner B. Paraxial protocadherin mediates cell sorting and tissue morphogenesis by regulating C-cadherin adhesion activity. The Journal of cell biology. 2006;174(2): 301-13. PMID: 16847104 | PMCID: PMC2064189
  • Vonica A, Gumbiner B. The Xenopus Nieuwkoop center and Spemann-Mangold organizer share molecular components and a requirement for maternal Wnt activity. Developmental biology. 2007;312(1): 90-102. PMID: 17964564 | PMCID: PMC2170525
  • Chen X, Molino C, Liu L, Gumbiner B. Structural elements necessary for oligomerization, trafficking, and cell sorting function of paraxial protocadherin. The Journal of biological chemistry. 2007;282(44): 32128-37. PMID: 17823115
  • Perrais M, Chen X, Perez-Moreno M, Gumbiner B. E-cadherin homophilic ligation inhibits cell growth and epidermal growth factor receptor signaling independently of other cell interactions. Molecular biology of the cell. 2007;18(6): 2013-25. PMID: 17392517 | PMCID: PMC1877107
  • Tsuiji H, Xu L, Schwartz K, Gumbiner B. Cadherin conformations associated with dimerization and adhesion. The Journal of biological chemistry. 2007;282(17): 12871-82. PMID: 17347145
  • Skoglund P, Rolo A, Chen X, Gumbiner B, Keller R. Convergence and extension at gastrulation require a myosin IIB-dependent cortical actin network. Development (Cambridge, England). 2008;135(14): 2435-44. PMID: 18550716 | PMCID: PMC2735133
  • Chen X, Koh E, Yoder M, Gumbiner B. A protocadherin-cadherin-FLRT3 complex controls cell adhesion and morphogenesis. PloS one. 2009;4(12): e8411. PMID: 20027292 | PMCID: PMC2791867
  • Xu C, Kim N, Gumbiner B. Regulation of protein stability by GSK3 mediated phosphorylation. Cell cycle (Georgetown, Tex.). 2009;8(24): 4032-9. PMID: 19923896 | PMCID: PMC2824240
  • Park K, Gumbiner B. Cadherin 6B induces BMP signaling and de-epithelialization during the epithelial mesenchymal transition of the neural crest. Development (Cambridge, England). 2010;137(16): 2691-701. PMID: 20610481 | PMCID: PMC2910385
  • Yoder M, Gumbiner B. Axial protocadherin (AXPC) regulates cell fate during notochordal morphogenesis. Developmental dynamics : an official publication of the American Association of Anatomists. 2011;240(11): 2495-504. PMID: 21960065 | PMCID: PMC3197877
  • Kim N, Koh E, Chen X, Gumbiner B. E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(29): 11930-5. PMID: 21730131 | PMCID: PMC3141988
  • Park K, Gumbiner B. Cadherin-6B stimulates an epithelial mesenchymal transition and the delamination of cells from the neural ectoderm via LIMK/cofilin mediated non-canonical BMP receptor signaling. Developmental biology. 2012;366(2): 232-43. PMID: 22537493 | PMCID: PMC3358420
  • Petrova Y, Spano M, Gumbiner B. Conformational epitopes at cadherin calcium-binding sites and p120-catenin phosphorylation regulate cell adhesion. Molecular biology of the cell. 2012;23(11): 2092-108. PMID: 22513089 | PMCID: PMC3364174