Pierre D. McCrea, Ph.D.

Background: Using cell and vertebrate model systems, our lab studies the catenin family of proteins. Catenins transduce developmental (Wnt and additional pathway) signals from the cytoplasm to the nucleus. Being multi-functional, catenins also bind cadherin cell-cell adhesion proteins at the plasma membrane as well as modulate Rho-family (small) GTPases participating in cytoskeletal control.

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 and delta-catenin. 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 in tubulogenic organs, the relative importance of canonical (beta-catenin mediated) versus non-canonical Wnt signals is uncertain. Through selective 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, since they 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: While functionally distinct entities, p120-catenin, ARVCF-catenin and delta-catenin share partial sequence homology with beta-catenin, and each is present in multiple cellular compartments. For example, each catenin binds to cadherin cell-cell adhesion proteins as well as to nuclear factors. In the nucleus, beta-catenin activates genes after binding to LEF/ TCF transcription factors, whereas p120-catenin and delta-catenin bind to Kaiso 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 interactions in development. Ultimately, we would like to address the extent to which catenin protein functions are networked to reach shared developmental objectives.

Selected Catenin Publications

Vaught TG*, Cho K*, Jennings JM, Kloc M, Gu D, Papasakelariou C, Ji H, Kowalczyk AP, McCrea PD. (2008) The desmosomal protein Kazrin interacts with ARVCF-catenin and shuttles between the nucleus and cytoplasm. J. Cell Science, in revision. (*co-first authorship)
Lyons JP, Zhou X, Weidinger G, Denayer T, Park JI, Ji H, Deroo T, Jones EA, Moon RT, Vleminckx K, Vize PD, McCrea PD. (2008) Wnt/ß-Catenin signaling is required for pronephric kidney tubule development. Mech. Dev., in revision.
McCrea PD, Park JI. (2007) Developmental functions of the p120-catenin sub-family. Biochim Biophys Acta, 1773:17–33.
Park JI, Ji H, Jun S, Gu D, Hikasa H, Li L, Sokol SY, McCrea PD. (2006) Frodo links Dishevelled to the p120-catenin/ Kaiso pathway: distinct catenin sub-families promote Wnt signals. Dev. Cell, 11:683–695.
van Roy FM, McCrea PD. (2005) A role for Kaiso-p120ctn complexes in cancer? Nature Reviews Cancer, 5:956–964.
Park J-I, Kim SW, Lyons JP, Ji H, Nguyen T, Cho K, Barton MC, Deroo T, Vleminckx K, Moon RT, McCrea PD. (2005) Kaiso/p120-catenin and TCF/β-catenin complexes coordinately regulate canonical Wnt gene targets. Dev. Cell, 8:843–854.
Fang X, Ji H, Kim S-W, Park J-I, Vaught TG, Anastasiadis PZ, Ciesiolka M, McCrea PD. (2004) Vertebrate development requires ARVCF- and p120-catenins and their interplay with RhoA and Rac. J. Cell Biol., 165:87–98.
Kim SW, Park JI, Spring CM, Sater AK, Ji H, Otchere AA, Daniel JM, McCrea PD. (2004) Non-canonical Wnt signals are modulated by the Kaiso transcriptional repressor and p120-catenin. Nature Cell Biol., 6:1212–20.
Lyons JP, Mueller UW, Ji H, Everett C, Fang X, Hsieh JC, Barth AIM, McCrea PD. (2004) Wnt-4 activates the canonical beta-catenin-mediated Wnt pathway and binds Frizzled-6 CRD: Functional implications of Wnt/ beta-catenin activity in kidney epithelial cells. Exp. Cell Res., 298:369–387.
Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang Z, Zhang R, Deng J, Behringer RR, McCrea PD, de Crombrugghe B. (2004) Interactions between Sox9 and β-catenin control chondrocyte differentiation. Genes & Devel., 18:1072–1087.
Tepera SB, McCrea PD, Rosen JM. (2003) A β-catenin survival signal is required for normal lobular development in the mammary gland. J. Cell Sci., 116:1137–1149.
Kim SW, Fang X, Ji H, Paulson AF, Daniel JM, Ciesiolka M, van Roy F, McCrea PD. (2002) Isolation and Characterization of xKaiso, a Transcriptional Repressor that Associates with the Catenin Xp120ctn in Xenopus laevis. J. Biol. Chem., 277:8202–8208.
Montross WT, Ji H, McCrea PD. (2000) A β-catenin-Engrailed chimera selectively suppresses Wnt signaling. J. Cell Sci., 113:1759–1770.
Paulson AF, Mooney EE, Fang X, Ji H, McCrea PD. (2000) Isolation and embryonic characterization of XARVCF: Xenopus member of the p120 catenin subfamily associating with cadherin membrane proximal domains. J. Biol. Chem., 275:30124–30131.
Paulson AF, Fang X, Ji H, Reynolds AB, McCrea PD. (1999) Misexpression of the p120(ctn)1A perturbs Xenopus gastrulation but does not elicit Wnt-directed axis specification. Dev. Biol., 207:350–363.