koonyee-lam@uiowa.edu
Mentor: Bryan Phillips, Ph.D.
Lab Room: 214 BBE
Lab Phone: 319-335-2072

Structure-function of SYS-1/β-catenin in Caenorhabditis elegans Wnt-directed asymmetric cell division

Wnt/β-catenin signaling is an essential component throughout the course of embryonic development and homeostasis of adult tissues, holding key roles in proliferation, control of stem cell population, and asymmetric differentiation. The Wnt/β-catenin (Wβ) pathway regulates binary fate specification via asymmetric cell division (ACD) in Caenorhabditis elegans. As in all Wβ pathways, the key to the worm pathway is β-catenin regulation. SYS-1/β-catenin is required for transcriptional activation of Wnt target genes and is regulated in a similar fashion as canonical β-catenin. ACD produces two daughter cells with different SYS-1 expression profiles; SYS-1 is highly expressed in the Wnt active daughter and SYS-1 expression is abolished in the Wnt inactive daughter. Although SYS-1 contains poor sequence conservation compared to vertebrate β-catenin, SYS-1 analyses reveal close structural and functional similarities with mammalian β-catenin. Similar to mammalian β-catenin, the SYS-1 crystal structure contains twelve armadillo repeats with a specific TCF binding domain. SYS-1 however, lacks C-terminal domain, which vertebrate β-catenin uses to recruit several transcriptional co-activators such as MED12 and CBP, in which worm homologs of these activators are required for proper ACD. Likewise, there is no identified GSK3β and CK1α binding site on SYS-1, although both GSK3β and CK1α kinases are essential for vertebrate β-catenin regulation. Therefore, the mechanism in which SYS-1 activates transcription of TCF genes as well as SYS-1 regulation remains elusive. The goal of my project is to employ a structure function approach to identify SYS-1 regulatory and transactivation domains, which will assist in identifying novel mechanisms of Wnt/β-catenin signaling regulation.

Lam AK, Phillips BT. Wnt Signaling Polarizes C. elegans Asymmetric Cell Divisions During Development. Results Probl Cell Differ. 2017;61:83-114. doi: 10.1007/978-3-319-53150-2_4. Review. PubMed PMID: 28409301.