Aims:  Our overall goal is to understand the cellular and developmental functions of catenins.1)  Reveal roles of the canonical Wnt pathway (beta-catenin mediated), as well as non-canonical Wnt pathways in animal development.2)  Examine the developmental functions of lesser understood catenins such as p120-catenin, ARVCF-catenin, delta-catenin and most recently plakophilin-3 (PKP3). Aim (2) occupies most of our laboratory’s current efforts. 

1) Beta-catenin:  A striking aspect of Wnt signaling is that it is important in multiple distinct contexts during embryogenesis and cancer progression, yet much remains to be learned.  For example, during Wnt-dependent morphogenesis of epithelial tubules, the relative importance of canonical (beta-catenin mediated) versus non-canonical Wnt signals is uncertain. Through inhibition of canonical Wnt signals in developing Xenopus embryos, we have observed defects in kidney tubulogenesis suggesting that canonical functions are required.  We now aim to address roles of non-canonical Wnt pathways, which cross-talk with the beta-catenin mediated pathway and are critical in the morphogenesis of diverse animal species.  While this work is centered upon kidney formation, our findings are likely to be relevant to other tubulogenic organs (such as lung, breast, prostate and pancreas), and to cancers that arise from the epithelial components of these tissues.  

2)  P120-Catenin, ARVCF-Catenin, Delta-Catenin & Plakophilin-3 (PKP3):   While functionally distinct entities, th p120-, ARVCF- , delta- and PKP3-catenins share partial sequence homology with beta-catenin, and each is present in multiple cellular compartments. For example, each binds to cadherin cell-cell adhesion proteins as well as nuclear factors. In the nucleus, beta-catenin activates genes after binding to LEF/ TCF transcription factors, whereas p120-catenin and delta-catenin bind to the Kaiso transcription factor to regulate gene activity. We recently revealed that complexes of beta-catenin/ TCF as well as p120-catenin/ Kaiso bind and directly regulate transcription from shared developmentally critical genes. Further upstream, we then discovered that p120-catenin interacts with Wnt-pathway modulators previously only known to associate with beta-catenin (such as Dishevelled and Frodo). To increase our understanding of ARVCF-catenin, we are characterizing its direct interaction with the novel protein Kazrin, which is little understood but in common with catenins localizes to both plasma-membrane and nuclear compartments. Further, we are examining novel delta-catenin and PKP3 interactions in development. Ultimately, we would like to address the extent to which catenin protein functions are networked to reach shared developmental objectives.