title: A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking.
abstract: The cation-independent mannose-6-phosphate receptor (CI-MPR) follows a highly regulated sorting itinerary to deliver hydrolases from the trans-Golgi network (TGN) to lysosomes. Cycling of CI-MPR between the TGN and early endosomes is mediated by GGA3, which directs TGN export, and PACS-1, which directs endosome-to-TGN retrieval. Despite executing opposing sorting steps, GGA3 and PACS-1 bind to an overlapping CI-MPR trafficking motif and their sorting activity is controlled by the CK2 phosphorylation of their respective autoregulatory domains. However, how CK2 coordinates these opposing roles is unknown. We report a CK2-activated phosphorylation cascade controlling PACS-1- and GGA3-mediated CI-MPR sorting. PACS-1 links GGA3 to CK2, forming a multimeric complex required for CI-MPR sorting. PACS-1-bound CK2 stimulates GGA3 phosphorylation, releasing GGA3 from CI-MPR and early endosomes. Bound CK2 also phosphorylates PACS-1Ser(278), promoting binding of PACS-1 to CI-MPR to retrieve the receptor to the TGN. Our results identify a CK2-controlled cascade regulating hydrolase trafficking and sorting of itinerant proteins in the TGN/endosomal system.
authors.affiliation: Vollum Institute, Oregon Health & Science University, Oregon Health Sciences University, Portland, 97239, USA.
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Scott
authors.forename: Hao
authors.initials: H
authors.lastname: Fei
authors.forename: Laurel
authors.initials: L
authors.lastname: Thomas
authors.forename: Guruprasad R
authors.initials: GR
authors.lastname: Medigeshi
authors.forename: Gary
authors.initials: G
authors.lastname: Thomas
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism*; D002417:Cattle; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000737:chemistry / Q000378:metabolism*; D013552:Swine; D014616:Vaccinia virus / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C407306:GGA adaptor proteins; D050505:Mutant Proteins; C491914:PACS1 protein, human; D017527:Receptor, IGF Type 2; D033921:Vesicular Transport Proteins; D047390:Casein Kinase II; D020727:ADP-Ribosylation Factors