Intracellular polarity protein PAR-1 regulates extracellular laminin assembly by regulating the dystroglycan complex

Cell polarity depends on extrinsic spatial cues and intrinsic polarity proteins including PAR-aPKC proteins. In mammalian epithelial cells, cell-cell contacts provide spatial cues that activate the aPKC-PAR-3-PAR-6 complex to establish the landmark of the initial cellular asymmetry. PAR-1, a downstream target of the aPKC-PAR-3-PAR-6 complex, mediates further development of the apical and basolateral membrane domains. However, the relationships between the PAR-aPKC proteins and other extrinsic spatial cues provided by the extracellular matrix (ECM) remain unclear.

Here, we show that PAR-1 is required for the assembly of extracellular laminin on the basal surface of mammalian cultured epithelial cell line, MDCK cells. PAR-1 is also indispensable for the basolateral localization of the dystroglycan (DG) complex, one of the laminin receptors essential for basement membrane formation, suggesting that PAR-1b affects extracellular laminin assembly by regulating this receptor complex. Consistently, loss of PAR-1 impairs the formation of a functional DG complex containing normally glycosylated alpha-DG and the spectrin-like actin-binding protein, utrophin. Furthermore, PAR-1 physically interacts with the DG complex through direct binding to the spectrin-like repeats of utrophin, and an alanine mutation of PAR-1-mediated phosphorylation sites on utrophin reduced the interaction between utrophin and dystroglycan.
These results reveal the presence of a novel inside-out pathway in which an intracellular polarity protein regulates the ECM organization required for epithelial cell polarity and tissue morphogenesis.

No relevant conflicts of interest declared.