Beyond Adhesion: Cadherin-Independent Control of Cancer Progression by p120-catenin

Chapter One provides a synopsis on the different functions of p120 in adhesion and beyond including stabilization of cadherin complexes, the regulation of Rho GTPases, and the transcriptional repressor Kaiso. In addition, it presents an overview of the context-dependent functions of p120 in tumor development and progression. In Chapter Two, we have investigated the subcellular localization of p120 and Kaiso, and their correlation with clinicopathological parameters in invasive breast cancer patients. Interestingly, the presence of nuclear Kaiso associated with breast cancer subtypes is linked to poor prognosis. Furthermore, the absence of E-cadherin expression and cytosolic p120 correlated with decreased nuclear Kaiso, which is indicative of a functional link between loss of adherens junction (AJ) function and transcriptional regulation in invasive breast cancer. In Chapter Three, we show that Kaiso-dependent transcriptional repression is relieved in ILC. In this setting, loss of E-cadherin leads to translocation of p120 to the nucleus where it binds and inhibits the transcriptional repressor Kaiso. Our data show that nuclear import of p120 is exacerbated in E-cadherin mutant ILC cells upon transfer to anchorage independence. Using genome-wide expression profiling of mouse (m)ILC cell lines, we identified known and novel Kaiso target genes, including Wnt11, a non-canonical Wnt ligand that controls anoikis resistance through induction of Rho signaling. As such we have identified the Kaiso target Wnt11 as a key upstream and autocrine cue driving activation of Rho-ROCK signaling in ILC cells. In Chapter Four, we identified Id2 as a novel Kaiso target gene and functionally characterized its role in anoikis resistance of ILC cells. We show that Id2 confers its oncogenic function through binding and inhibition of the pro-apoptotic tumor suppressor Rb. Chapter Five, reports on a novel function of p120 in the regulation of cytokinesis. Using conditional mouse models based on inactivation of p120 in combination with p53 loss, we show that loss of p120 is causal to the formation of chromosomally unstable multinucleated cancer cells. Furthermore, we have unraveled a mechanism in which p120 regulates spatiotemporal RhoA activity at the equatorial cortex through binding to the centralspindlin component MKLP1. Subsequent loss of p120 expression leads to deregulated and non-focused RhoA activity during anaphase and leads to cytokinesis failure and the generation of multinucleated cells. Together, our results show that loss of p120 may contribute to tumor progression over two distinct pathways: (i) loss of adhesion and (ii) induction of chromosomal instability. Chapter Six provides an overview of the shared mechanisms in regulation of RhoA signaling in cellular adhesion and cytokinesis, two distinct processes that depend on actomyosin contractility