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Cara Gottardi, PhDAssistant Professor
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The ability of individual cells to adhere and coalesce into distinct tissue structures is a major feature of multicellular organisms. Research in my laboratory centers on a protein complex that projects from the cell surface and forms a structural “Velcro” that holds cells to one another. This complex is comprised of a transmembrane “cadherin” component which mediates Ca++-dependent homophilic recognition, and a number of associated “catenins” which link cadherins to the underlying cytoskeleton. A major focus in our field is to understand how these catenins modulate the cadherin, and hence, cell-cell adhesiveness. Mutations within cadherin/catenin components are widely appreciated to play causal roles in tumor initiation and metastasis, but precise molecular mechanisms remain to be elucidated. Towards this end, we seek to understand how E-cadherin “signaling” mediates invasion suppression in a human breast cancer cell model.
b-catenin, in addition to being a critical component for robust cell-cell adhesion, also plays an essential role in regulating gene expression in response to extracellular Wnt ligands. Gene activation is ultimately controlled by the formation of a binary transcription complex that contains the DNA binding factor, T-Cell Factor (TCF), and b-catenin. We seek to understand how cell-cell adhesion and gene expression are coordinated through this common component, b-catenin, so that these processes can be, at times, interrelated, while at other times, independent, during various developmental processes. Preliminary data shows that a form of b-catenin can be generated during Wnt signaling that preferentially binds to the transcription factor, TCF, but not cadherin-type adhesion receptors. This signaling form is monomeric and is regulated by the C-terminus of b-catenin, which selectively competes cadherin binding through an intramolecular fold-back mechanism. Phosphorylation of the cadherin reverses the TCF binding selectivity, suggesting another potential layer of regulation. In contrast, the main cadherin-binding form of b-catenin is a dimeric complex of b-catenin bound to another partner, a-catenin. We intend to identify the molecular signals and machinery that control these distinct forms of b-catenin. We hypothesize that protein modification (such as phosphorylation) controls b-catenin binding to cadherin and a-catenin, and intend to identify the sites that control these binding activities using in vitro kinase and phosphopeptide mapping strategies. We propose to elucidate the cellular machinery (i.e., kinases, phosphatases and scaffold proteins) that modulate b-catenin binding to cadherin or a-catenin by targeting hypothesized regulatory components using the RNAi ‘knock-down’ strategy.
As b-catenin exhibits both tumor suppressor and oncogenic activities depending on its binding partner (cadherin or TCF, respectively), understanding how these complexes are assembled and regulated will form the basis for therapeutic strategies that either enhance the tumor-inhibiting properties of b-catenin, or inhibit the tumor-promoting properties of b-catenin in human cancers.
Gottardi, C. J., E. Wong and B. M. Gumbiner. 2001. E-cadherin suppresses cell transformation by inhibiting b-catenin signaling in an adhesion-independent manner. J. Cell Biol. 153, 1049-1060.
Gottardi, C.J. and B. M. Gumbiner. 2004. Role for ICAT (Inhibitor of catenin and TCF) in b-catenin-dependent nuclear signaling and cadherin functions. Am J Physiol Cell Physiol 286: C747--C756, 2004 (e-publication: November 12, 2003).
Gottardi, C.J. and B. M. Gumbiner. 2004. Distinct molecular forms of b-catenin are targeted to adhesive or transcriptional complexes. J. Cell Biol. In press.
Reinacher-Schick, A. and C.J. Gottardi. The b-catenin signaling inhibitor, ICAT, is up-regulated in colorectal tumors. In preparation
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View Publications by Cara Gottardi listed in the National Library of Medicine (PubMed). |
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