Tyrosine-based Signals Converge on Daple•PARD3 Complex to Fine-tune Polarized Planar Cell Migration

Polarized distribution of organelles and molecules inside a cell is vital for a range of cellular processes and its loss is frequently encountered in disease. Polarization during planar cell migration is a special condition in which cellular orientation is triggered by cell-cell contact. Here, we demonstrate that the multi-modular signaling scaffold Daple (CCDC88C) is a component of cell junctions in epithelial cells which serves like a cellular 9compass9 for establishing and maintaining contact-triggered planar polarity via its interaction with the polarity regulator PARD3. This interaction, mediated by Daple9s PDZ-binding motif (PBM) and the third PDZ domain of PARD3, is fine-tuned by two tyrosine phosphoevents on Daple9s PBM that are triggered by a multitude of growth factors. Hypophosphorylation strengthens the interaction, whereas hyperphosphorylation disrupts it. These findings reveal an unexpected role of Daple within the planar cell polarity pathway as a platform for signal integration and gradient sensing for tyrosine-based signals.