The phosphorylation state of an autoregulatory domain controls PACS-1-directed protein traffic
Open Access
- 1 December 2003
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 22 (23), 6234-6244
- https://doi.org/10.1093/emboj/cdg596
Abstract
PACS‐1 is a cytosolic sorting protein that directs the localization of membrane proteins in the trans‐Golgi network (TGN)/endosomal system. PACS‐1 connects the clathrin adaptor AP‐1 to acidic cluster sorting motifs contained in the cytoplasmic domain of cargo proteins such as furin, the cation‐independent mannose‐6‐phosphate receptor and in viral proteins such as human immunodeficiency virus type 1 Nef. Here we show that an acidic cluster on PACS‐1, which is highly similar to acidic cluster sorting motifs on cargo molecules, acts as an autoregulatory domain that controls PACS‐1‐directed sorting. Biochemical studies show that Ser278 adjacent to the acidic cluster is phosphorylated by CK2 and dephosphorylated by PP2A. Phosphorylation of Ser278 by CK2 or a Ser278→Asp mutation increased the interaction between PACS‐1 and cargo, whereas a Ser278→Ala substitution decreased this interaction. Moreover, the Ser278→Ala mutation yields a dominant‐negative PACS‐1 molecule that selectively blocks retrieval of PACS‐1‐regulated cargo molecules to the TGN. These results suggest that coordinated signaling events regulate transport within the TGN/endosomal system through the phosphorylation state of both cargo and the sorting machinery.Keywords
This publication has 120 references indexed in Scilit:
- Role of PACS-1 in Trafficking of Human Cytomegalovirus Glycoprotein B and Virus ProductionJournal of Virology, 2003
- Signals for Sorting of Transmembrane Proteins to Endosomes and LysosomesAnnual Review of Biochemistry, 2003
- Phosphorylation-induced Conformational Changes Regulate GGAs 1 and 3 Function at the Trans-Golgi NetworkPublished by Elsevier BV ,2003
- Furin at the cutting edge: From protein traffic to embryogenesis and diseaseNature Reviews Molecular Cell Biology, 2002
- The endocytic pathway: a mosaic of domainsNature Reviews Molecular Cell Biology, 2001
- Regulation of Endosome Sorting by a Specific PP2A IsoformThe Journal of cell biology, 1998
- The Transcriptional Coactivators p300 and CBP Are Histone AcetyltransferasesCell, 1996
- A CBP Integrator Complex Mediates Transcriptional Activation and AP-1 Inhibition by Nuclear ReceptorsCell, 1996
- Transcriptionally active chimeric gene derived from the fusion of the AML1 gene and a novel gene on chromosome 8 in t(8;21) leukemic cellsCancer Genetics and Cytogenetics, 1992
- Premature expression of the macrophage colony-stimulating factor receptor on a multipotential stem cell line does not alter differentiation lineages controlled by stromal cells used for coculture.The Journal of Experimental Medicine, 1991