Planar cell polarity (PCP) is defined as a polarization process in which cells are polarized along the plane of the tissue. PCP plays important roles in many developmental processes and defects in PCP cause various diseases including cancer metastasis. PCP is regulated by signaling receptors which are asymmetrically localized in cell boundaries. Newly synthesized PCP proteins are delivered along the secretory transport pathway from the endoplasmic reticulum (ER) to the plasma membrane. However, the molecular mechanisms that regulate this transport process remain largely unclear. Here, we analyzed the export of a PCP protein, Frizzzled6, out of the ER. Using protein interaction analysis, we found that Frizzled6 contains two conserved polybasic motifs: one located on its first int...[ Read more ]

Planar cell polarity (PCP) is defined as a polarization process in which cells are polarized along the plane of the tissue. PCP plays important roles in many developmental processes and defects in PCP cause various diseases including cancer metastasis. PCP is regulated by signaling receptors which are asymmetrically localized in cell boundaries. Newly synthesized PCP proteins are delivered along the secretory transport pathway from the endoplasmic reticulum (ER) to the plasma membrane. However, the molecular mechanisms that regulate this transport process remain largely unclear. Here, we analyzed the export of a PCP protein, Frizzzled6, out of the ER. Using protein interaction analysis, we found that Frizzled6 contains two conserved polybasic motifs: one located on its first intracellular loop and the other located on its C-terminal cytosolic domain. These motifs are important for the interaction between Frizzled6 and the Coat protein complex II (COPII) coat, an important protein complex that regulates packaging cargo proteins at the ER. We found that a synthetic peptide that corresponded to the first intracellular loop of Frizzled6 inhibited interactions between COPII and Frizzled6 and blocked vesicular release of Frizzled6. These results demonstrate the importance of the polybasic motif for ER export of Frizzled6. We also identified two N-glycosylation sites on the luminal domain of Frizzled6, which are important for ER export of Frizzled6. Moreover, our data indicate that another PCP receptor, Celsr1 is in the same vesicle with Frizzled6, suggesting that these two PCP proteins are associated with each other in the early secretory transport pathway en route to their final destinations. Taken together, these results reveal an insight into the molecular machinery that regulates ER export of Frizzled6.