About Dr. McCrea
Dr. McCrea is a Professor in the Department of Genetics. His laboratory seeks to reveal the biology of varied catenin proteins in primary cell/ cell line settings as well as in vivo, with the latter involving amphibian embryos to ease the viewing and manipulation of all vertebrate embryonic stages. The group's research spans the roles of catenins in nuclear gene control ( e.g. via Wnt-pathway modulation), their involvement in cytoskeletal control ( e.g. via small-GTPases), and their interactions with novel entities or cell junctional complexes ( e.g. cadherin-catenin functions). The lab's long-range purpose is to understand how the roles of catenins are networked in normal development and disease states such as cancer. Dr. McCrea is additionally active in efforts that promote graduate and postdoctoral training and mentorship.
Professor, Department of Genetics, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX
Catenin biology Stem Cells Neural Development Early Vertebrate Development Intracellular and Nuclear Signaling
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.
|1987||Yale University, New Haven, CT, USA, PHD, Molecular Biophysics and Biochemistry|
|1981||Yale University, New Haven, CT, USA, M.PHIL, Molecular Biophysics and Biochemistry|
|1979||Bowdoin College, Brunswick, ME, USA, AB, Biochemistry|
|1993-1993||Postdoctoral Associate, Cellular Biochemistry and Biophysics Program, Sloan-Kettering Cancer Institute, New York, NY|
|1988-1992||Postdoctoral Fellow, Cell and Developmental Biology, University of California-San Francisco, San Francisco, CA|
|1987-1988||Postdoctoral Associate, Molecular Biophysics and Biochemistry, Yale University, New Haven, CT|
|2016||Paul E. Darlington Mentor Award, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences|
- Jun S, Jung YS, Suh HN, Wang W, Kim MJ, Oh YS, Lien EM, Shen X, Matsumoto Y, McCrea PD, Li L, Chen J, Park JI. LIG4 Mediates Wnt Signaling-Induced Radioresistance. Nat Commun 7:10994, 2016. e-Pub 2016. PMID: 27009971.
- Hong JY, Oh IH, McCrea PD. Phosphorylation and isoform use in p120-catenin during development and tumorigenesis. Biochim Biophys Acta 1863(1):102-14, 2016. e-Pub 2015. PMID: 26477567.
- McCrea PD, Gottardi CJ. Beyond β-catenin: prospects for a larger catenin network in the nucleus. Nat Rev Mol Cell Biol 17(1):55-64, 2016. e-Pub 2015. PMID: 26580716.
- Wang W, Li X, Lee M, Jun S, Aziz KE, Feng L, Tran MK, Li N, McCrea PD, Park JI, Chen J. FOXKs Promote Wnt/β-Catenin Signaling by Translocating DVL into the Nucleus. Dev Cell 32(6):707-18, 2015. PMID: 25805136.
- McCrea PD, Maher MT, Gottardi CJ. Nuclear signaling from cadherin adhesion complexes. Curr Top Dev Biol 112:129-96, 2015. e-Pub 2015. PMID: 25733140.
- Lee M, Ji H, Furuta Y, Park JI, McCrea PD. P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation. J Cell Sci 127(Pt 18):4037-51, 2014. e-Pub 2014. PMID: 25074806.
- Munoz WA, Lee M, Miller RK, Ahmed Z, Ji H, Link TM, Lee GR, Kloc M, Ladbury JE, McCrea PD. Plakophilin-3 catenin associates with the ETV1/ER81 transcription factor to positively modulate gene activity. PLoS One 9(1):e86784, 2014. e-Pub 2014. PMID: 24475179.
- Hong JY, Park JI, Lee M, Muñoz WA, Miller RK, Ji H, Gu D, Sokol SY, McCrea PD. Down's-syndrome-related kinase Dyrk1A modulates the p120-catenin-Kaiso trajectory of the Wnt signaling pathway. J Cell Sci 125(Pt 3):561-9, 2012. PMID: 22389395.
- Munoz WA, Kloc M, Cho K, Lee M, Hofmann I, Sater A, Vleminckx K, McCrea PD. Plakophilin-3 is required for late embryonic amphibian development, exhibiting roles in ectodermal and neural tissues. PLoS One 7(4):e34342, 2012. e-Pub 2012. PMID: 22496792.
- Gu D, Tonthat NK, Lee M, Ji H, Bhat KP, Hollingsworth F, Aldape KD, Schumacher MA, Zwaka TP, McCrea PD. Caspase-3 cleavage links delta-catenin to the novel nuclear protein ZIFCAT. J Biol Chem 286(26):23178-88, 2011. e-Pub 2011. PMID: 21561870.
- Hong JY, Park JI, Cho K, Gu D, Ji H, Artandi SE, McCrea PD. Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members. J Cell Sci 123(Pt 24):4351-65, 2010. e-Pub 2010. PMID: 21098636.
- Gu D, Sater AK, Ji H, Cho K, Clark M, Stratton SA, Barton MC, Lu Q, McCrea PD. Xenopus delta-catenin is essential in early embryogenesis and is functionally linked to cadherins and small GTPases. J Cell Sci 122(Pt 22):4049-61, 2009. e-Pub 2009. PMID: 19843587.
- Park JI, Ji H, Jun S, Gu D, Hikasa H, Li L, Sokol SY, McCrea PD. Frodo links Dishevelled to the p120-catenin/Kaiso pathway: distinct catenin subfamilies promote Wnt signals. Dev Cell 11(5):683-95, 2006. PMID: 17084360.
- Park JI, Kim SW, Lyons JP, Ji H, Nguyen TT, Cho K, Barton MC, Deroo T, Vleminckx K, Moon RT, McCrea PD. Kaiso/p120-catenin and TCF/beta-catenin complexes coordinately regulate canonical Wnt gene targets. Dev Cell 8(6):843-54, 2005. PMID: 15935774.
- Kim SW, Park JI, Spring CM, Sater AK, Ji H, Otchere AA, Daniel JM, McCrea PD. Non-canonical Wnt signals are modulated by the Kaiso transcriptional repressor and p120-catenin. Nat Cell Biol 6(12):1212-20, 2004. e-Pub 2004. PMID: 15543138.