A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking

EMBO J. 2006 Oct 4;25(19):4423-35. doi: 10.1038/sj.emboj.7601336. Epub 2006 Sep 14.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADP-Ribosylation Factors / metabolism*
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Amino Acid Sequence
  • Animals
  • Casein Kinase II / metabolism*
  • Cattle
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Molecular Sequence Data
  • Mutant Proteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Transport
  • Rats
  • Receptor, IGF Type 2 / chemistry
  • Receptor, IGF Type 2 / metabolism*
  • Swine
  • Vaccinia virus / physiology
  • Vesicular Transport Proteins / chemistry
  • Vesicular Transport Proteins / metabolism*
  • trans-Golgi Network / metabolism


  • Adaptor Proteins, Vesicular Transport
  • GGA adaptor proteins
  • Mutant Proteins
  • PACS1 protein, human
  • Receptor, IGF Type 2
  • Vesicular Transport Proteins
  • Casein Kinase II
  • ADP-Ribosylation Factors