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Arrestin-2 interacts with the endosomal sorting complex required for transport machinery to modulate endosomal sorting of CXCR4. Mol Biol Cell 2010 Jul 15;21(14):2529-41

Date

05/28/2010

Pubmed ID

20505072

Pubmed Central ID

PMC2903679

DOI

10.1091/mbc.E10-02-0169

Scopus ID

2-s2.0-77954626403   70 Citations

Abstract

The chemokine receptor CXCR4, a G protein-coupled receptor, is targeted for lysosomal degradation via a ubiquitin-dependent mechanism that involves the endosomal sorting complex required for transport (ESCRT) machinery. We have reported recently that arrestin-2 also targets CXCR4 for lysosomal degradation; however, the molecular mechanisms by which this occurs remain poorly understood. Here, we show that arrestin-2 interacts with ESCRT-0, a protein complex that recognizes and sorts ubiquitinated cargo into the degradative pathway. Signal-transducing adaptor molecule (STAM)-1, but not related STAM-2, interacts directly with arrestin-2 and colocalizes with CXCR4 on early endosomal antigen 1-positive early endosomes. Depletion of STAM-1 by RNA interference and disruption of the arrestin-2/STAM-1 interaction accelerates agonist promoted degradation of CXCR4, suggesting that STAM-1 via its interaction with arrestin-2 negatively regulates CXCR4 endosomal sorting. Interestingly, disruption of this interaction blocks agonist promoted ubiquitination of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) but not CXCR4 and STAM-1 ubiquitination. Our data suggest a mechanism whereby arrestin-2 via its interaction with STAM-1 modulates CXCR4 sorting by regulating the ubiquitination status of HRS.

Author List

Malik R, Marchese A

Author

Adriano Marchese PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Arrestins
Binding Sites
Cell Line
Endosomal Sorting Complexes Required for Transport
Endosomes
Humans
Models, Biological
Phosphoproteins
Protein Binding
Protein Interaction Mapping
Protein Structure, Tertiary
Protein Transport
Receptors, CXCR4
Ubiquitination
beta-Arrestins