Role of PIPKIγ in the epithelial-mesenchymal transition (EMT) and cancer metastasis

Despite the importance of PI4,5P2 to cell morphology and migration, role of its generator in cancer progression and tumor metastasis is underestimated compared to other lipid signaling molecules such as PI3K, PTEN and PLCs. EMT, the hallmark of tumor metastasis, is a two-step morphology transition requiring loss of epithelial characteristics and acquisition of migration ability. We have observed that PIPKIγ associates with talin (in fibroblast) and E-cadherin (in epithelial cells) and regulates their assembly into cell-matrix adhesions and cell-cell adhesions, respectively. This is potentially biophysically significant. We hypothesize that PIPKIγ plays a critical role in epithelial morphogenesis and malfunction of PIPKIγ participates in EMT. In particular, we propose that when relocated from epithelial cell-cell adhesions to cell-matrix adhesions via abnormal modifications, PIPKIγ switches roles from maintaining the epithelial phenotype to enhancing the cell mobility, and promotes the progression of EMT. Related to this, proteins regulating function and localization of PIPKIγ may be critical for EMT and metastasis.

The objective of this proposal is to define the mechanisms for PIPKIγ to modulate the morphology and motility of breast epithelial cells. The physiological significance of PIPKIγ interacting with cadherins and talin in breast epithelial cells will be investigated. More importantly, we will determine how malfunction and/or mis-regulation of PIPKIγ could promote the progression of EMT.