Catenin biology; stem cells; neural development; early vertebrate development; intracellular and nuc
MD Anderson Cancer Center
The University of Texas
MD Anderson Cancer Center
1515 Holcombe Blvd
General/Lab Fax: (713) 834-6291
McCrea, Pierre 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 (e.g. at cell-cell junctions), as well as modulate Rho-family (small) GTPases participating in cytoplasmic cytoskeletal control. Goals: We wish to understand the roles of catenins at both developmental and mechanistic levels. In particular our group addresses: 1) lesser-understood catenins such as p120-catenin, ARVCF-catenin, delta-catenin and plakophilin-3 (PKP3); and 2) their involvement in Wnt or other signaling pathways relevant to stemness, differentiation or homeostasis/ regeneration. While functionally distinct entities, the 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 the TCF/ LEF transcription factors, whereas p120-catenin or delta-catenin (etc.) bind to other transcription factors to regulate gene activity. We recently revealed that complexes of p120-catenin/Kaiso as well as of beta-catenin/TCF directly regulate transcriptional activity at shared developmentally critical genes. Further upstream, we then discovered that p120-catenin interacts with canonical-Wnt pathway modulators only previously known to associate with beta-catenin (e.g. "destruction-complex" components such as Axin, as well as more upstream entities such as Dishevelled and Frodo). Currently, we are evaluating an exciting unexpected interaction of p120-catenin with a powerful transcriptional complex well known to participate in stemness/ differentiation decisions. To widen our understanding of catenin biology, we have further examined additional catenins. For example, we showed that ARVCF is essential in Xenopus development and characterized 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, modulating small-GTPases and potentially gene regulatory functions. We have also probed delta-catenin's roles, and revealed surprisingly, that it is positively regulated by caspase3 cleavage (caspase3 is known to operate also in non-apoptotic settings), generating a large fragment which enters the nucleus to bind, and we expect modulate, a novel Krab-domain zinc-finger repressor we named ZIFCAT. Most recently, we resolved PKP3-catenin's interaction with ETV1, a DNA-binding transcriptional activator important in neural development (dopaneurgic-pathway, etc.), whose activity is positively enhanced by PKP3. In the coming years, we aim to confront the larger question as to the extent that catenin nuclear functions are networked or distinct in reaching developmental objectives.