The cation-independent mannose-6-phosphate receptor (CI-MPR) cycles between the trans-Golgi network and endosomes to mediate lysosomal hydrolase trafficking, a process regulated by the adaptor proteins GGA3 and PACS-1. Although both bind a CK2-phosphorylated acidic cluster motif on CI-MPR, they direct opposing sorting steps. This study identifies autoregulatory acidic cluster domains in PACS-1 and GGA3 that are differentially controlled by CK2 phosphorylation. PACS-1 links CK2 to GGA3, forming a complex that coordinates CI-MPR release, retrieval, and recycling. These findings reveal a CK2-driven phosphorylation cascade that orchestrates endosomal–Golgi protein trafficking.
