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PMID: 20505072 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Arrestin-2 interacts with the endosomal sorting complex required for transport machinery to modulate endosomal sorting of CXCR4.

Molecular biology of the cell ·Vol. 21 ·No. 14 ·2010-07-15 ·Pages 2529-41

Malik R, Marchese A

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/metabolism Arrestins/chemistry,metabolism Binding Sites Cell Line Endosomal Sorting Complexes Required for Transport/metabolism Endosomes/metabolism Humans Models, Biological Phosphoproteins/metabolism Protein Binding Protein Interaction Mapping Protein Structure, Tertiary Protein Transport Receptors, CXCR4/metabolism Ubiquitination beta-Arrestins
Chemicals
Adaptor Proteins, Signal Transducing Arrestins Endosomal Sorting Complexes Required for Transport Phosphoproteins Receptors, CXCR4 STAM protein, human beta-Arrestins hepatocyte growth factor-regulated tyrosine kinase substrate
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Malik Rohit
Program in Molecular Biology and Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Marchese Adriano
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1939-4586
DOI
10.1091/mbc.e10-02-0169
Published
2010-07-15
Epub
2010-00-26
Pages
2529-41
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC2903679
Subset
IM
Grants
NIDA NIH HHS · R01 DA026040 · United States
NIGMS NIH HHS · R01 GM075159 · United States
NIGMS NIH HHS · R01 GM075159-05 · United States
NIGMS NIH HHS · GM-75159 · United States
External Links
PubMed source DOI: 10.1091/mbc.e10-02-0169 PMC Full Text View journal details
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