PIPKIγ and talin couple phosphoinositide and adhesion signaling to control the epithelial to mesenchymal transition

Epithelial cells acquire migratory/invasive and stemness traits upon conversion to the mesenchymal phenotype. The expression of E-cadherin is a key to this transition; yet precise understanding of the pathways involved in integrating E-cadherin loss to the gain of mesenchymal traits remains poorly understood. Here, we show that phosphoinositide-generating enzyme, PIPKI gamma, expression is upregulated upon epithelial-mesenchymal transition (EMT) and together with the cytoskeletal protein talin assemble into a signaling complex upon E-cadherin loss. PIPKI gamma and talin together control the adhesion and phosphoinositide signaling that regulates conversion to the mesenchymal phenotypes. PIPKI gamma and talin regulate the stability of E-cadherin transcriptional repressors, snail and slug, induced by transforming growth factor-beta 1 or extracellular matrix protein. Loss of PIPKI gamma or talin or their interaction impaired EMT and the acquisition of cell motility and stemness. This demonstrates a mechanism where a phosphoinositide-generating enzyme PIPKI gamma couples with a cytoskeletal protein talin to control the acquisition of mesenchymal phenotypes.