Delineating the Function and Regulation of Vangl2 in Epithelial-to-mesenchymal Transition (EMT)
DescriptionEpithelial-to-mesenchymal transition (EMT) is a remarkable example of cellular plasticity that involves a conversion of cellular identity from epithelium to mesenchyme. As an essential developmental process in multicellular organisms, EMT is also hijacked by the malignant cancer cells to acquire invasive and metastatic capacity. At the cellular level, dissolution of epithelial polarity is a hallmark of EMT controlled by an intricate signaling network that includes the TGF-bpathway. Interestingly, many signaling components of epithelial polarity are functionally involved in EMT. For example, a series of apical-basal polarity proteins have been shown to mediate the EMT-associated structural reorganization. In contrast, it remains elusive about how planar cell polarity (PCP), the epithelial asymmetry perpendicular to the apical-basal axis, is functionally implicated in EMT.Vangl2, a core component of PCP signaling, plays a critical role in regulating tissue architecture and morphogenesis. Aberrant Vangl2 upregulation is frequently observed in human malignancy, however the mechanism remains unknown. Interestingly, our preliminary studies revealed that TGF-b-induced EMT is accompanied by a significant induction of Vangl2 expression, which is necessary for the dissolution of epithelial polarity. Moreover, ectopic Vangl2 expression is sufficient to disrupt epithelial polarity and promote TGF-b-induced EMT. To explore the mechanisms underlying the function of Vangl2, our proteomic characterization revealed that Vangl2 interacts with PKCVand disassembles the PAR protein complex, a key regulator of the apical-basal polarity. Notably, our preliminary data indicate that TGF-binduces the formation of Vangl2-PKCVcomplex.These observations prompt us to hypothesize that the Vangl2-PKCVcomplex plays a critical role in regulating EMT. To address this hypothesis, we will employ multidisciplinary approaches that integrate biochemical analyses with microscopy imaging to address two specific aims. We will first delineate the molecular mechanisms of how Vangl2 interacts with PKCVto promote the dissolution of PAR complex and epithelial polarity. In the second aim, we will investigate the integration of Vangl2-PKCVwith TGF-bsignaling during the induction of EMT. Outcomes of these studies will provide novel mechanistic insights into the role of PCP signaling in EMT and will define novel molecular and functional mechanisms of the integration between PCP and apical-basal polarity pathways. Moreover, our studies will provide key underpinnings for designing therapeutic strategies that target EMT, which is closely implicated in cancer invasion and metastasis.
|Effective start/end date||1/01/19 → …|