Model for the trafficking of polycystin-2 to the primary cilium. Most of the wild-type polycystin-2 protein leaves the ER in a COPII-dependent fashion and is rapidly returned from the Golgi apparatus due to the presence of a 34–amino acid retrieval signal in its C terminus (dark blue arrows). A small portion of wild-type polycystin-2 will reach the cis-Golgi apparatus (red arrow) and is diverted to the primary cilium (orange arrow), where the delivery is controlled by Rab8a. Whether the ciliary targeting signal “RVxP” in the N terminus of polycystin-2 acts at the cis-Golgi compartment or at a more distal location is not known. Under some circumstances, e.g., due to the interaction between polycystin-2 and polycystin-1 or upon the loss of the retrieval signal in the C terminus, polycystin-2 will also reach the somatic plasma membrane through the Golgi apparatus (light blue arrow). Passage through the Golgi apparatus depends on the “KxxxF” motif in loop 4.