Disruptions in cell polarity and morphology often lead to the disorganization of normal tissue architecture. Identifying novel genes and pathways that prevent this tipping point from normal to transformed cells can shed light on the mechanisms that cause the initiation and progression of epithelial cancers.
Recently, our lab identified ZYG11A as a novel regulator of mammalian epithelial cell morphology. Although a role for ZYG11A and the other highly conserved ZYG11 family members, ZYG11B and ZER1, has been described in cell cycle control and viral oncoprotein function, little is known about how these genes contribute to the regulation of cell polarity and morphology in mammalian systems.
To investigate the function of ZYG11 family members in mammalian epithelial cell organization, we have used a combination of gene expression, live-cell imaging, and high throughput functional analysis in MCF10A cells.
Our studies provide evidence for divergent functions in cell migration, cell cycle and cell viability for individual ZYG11 family members, where the loss of ZYG11A results in more severe phenotypic outcomes. As a substrate recognition subunit for the CUL2 E3 ubiquitin ligase, ZYG11A is likely to specify the turnover of various proteins. Therefore, a better understanding of the ubiquitination targets of ZYG11A is paramount. Using an RNAi rescue screen we have identified key adhesion, polarity, and degradation related proteins as potential targets of ZYG11A regulation. Complementary studies using proximity biotinylation have outlined a larger, previously unknown network of ZYG11A interacting proteins, including hits related to the extracellular matrix and the actin cytoskeleton.
This study provides important insights into the individual function of each ZYG11 family member and highlights key proteins that ZYG11A may regulate. These potential ubiquitination targets are crucial in identifying how the ZYG11 family regulates cell polarity and morphology, and how this may ultimately regulate the initiation and progression of epithelial cancer.