Dr. Pierre D. McCrea
The University of Texas MD Anderson Cancer Center
Department of Genetics
Catenin contributions in cell and developmental biology.
Using primary neurons, developing frog embryos and cell lines, we seek to understand the biology of essential catenin proteins. Catenins transduce developmental (e.g. canonical-Wnt pathway) and pathologic signals into the nucleus. Being multi-functional, they further bind and modulate cadherins in regulating cell-cell adhesion at junctions, and influence small-GTPases that determine the behavior of cytoskeletal structures, cell shape and cell movements. Many key interactions and functions of the catenins are yet to be discovered.
We are asking how the catenins within cells help to advance vertebrate development, for example:
1) How are the shapes of neuronal dendrites modulated by delta-catenin and its protein partners?
1) Beyond beta-catenin, do multiple catenins act in parallel to promote canonical-Wnt signaling?
2) What are the distinct versus shared functions of catenins in the nucleus?
All catenins with one exception shares homology with the best-known family member, beta-catenin, and each catenin acts in a number of cell compartments. If we first consider the nucleus, beta-catenin binds to transcription factors such as TCF/ LEF in response to Wnt signals, leading to gene-target activation. We have revealed that less-understood catenins - our primary interest - likewise bind to key known or novel transcriptional complexes. For example, p120-catenin regulates genes that are instrumental in development and cancer, and we find that similar upstream controls act upon p120-isoform1 as beta-catenin. We also uncovered novel transcriptional complexes involving plakophilin3-catenin, delta-catenin, and p120-catenin, with the latter potentially involved in decisions of neural stemness versus differentiation. Our current work upon delta-catenin instead centers on its actions outside the nucleus. We find that delta-catenin contains a phospho-switch at its C-terminus that “decides” between delta’s binding of one of two novel scaffolding proteins in neurons. We postulate that each outcome differentially alters the cytoskeleton to favor either dendrite elongation versus branching. Given the need to regulate neural connectivity (e.g. interactions of dendrites with axons), this key decision process must be properly executed countless times during the formation of the nervous system, and it is altered in prominent neurologic pathologies. In the longer term, we aspire to address the extent to which the functions of catenins are networked to meet an array of cellular and developmental goals.