Par1b controls cell polarity by phosphorylating an actin-regulatory protein to inhibit cells’ interactions with the extracellular matrix, Cohen et al. reveal.

Par1b is a kinase that regulates the polarity of many different cell types. MDCK kidney epithelial cells, for example, fail to adhere to each other or polarize correctly in the absence of the kinase. Par1b overexpression, on the other hand, causes kidney cells to relocalize their lumens from their apical domains to the lateral membranes between neighboring cells, an orientation normally found only in liver epithelia.

Cohen et al. screened for new Par1b substrates and identified IRSp53, an adaptor protein that links Rho GTPases to downstream promoters of actin polymerization. MDCK cells lacking IRSp53 formed lateral lumens similar to cells overexpressing Par1b. Yet IRSp53 knockdown had no effect on intercellular adhesion. Instead, IRSp53 depletion inhibited cell–matrix interactions, reducing cell spreading, focal adhesion formation, and basal lamina deposition. Par1b overexpression also inhibited cell spreading but a nonphosphorylatable form of IRSp53 reversed this phenotype and restored lumen formation to the apical surface.

Par1b thus regulates cell polarity by inhibiting IRSp53’s control of cell–extracellular matrix signaling. Par1b phosphorylation prompted IRSp53 to preferentially bind 14-3-3 adaptor proteins instead of actin regulators, potentially inhibiting the Rho GTPase signaling pathways that control the interactions of cells with their surrounding matrix. Senior author Anne Müsch now wants to identify the precise pathways blocked by Par1b and to understand how this results in lumen repositioning.

et al
J. Cell Biol.