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Endosomal deubiquitinating enzymes control ubiquitination and down-regulation of protease-activated receptor 2

Hasdemir, B., Murphy, J. E., Cottrell, G. S. and Bunnett, N. W. (2009) Endosomal deubiquitinating enzymes control ubiquitination and down-regulation of protease-activated receptor 2. Journal of Biological Chemistry, 284 (41). pp. 28453-28466. ISSN 1083-351X

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To link to this item DOI: 10.1074/jbc.M109.025692

Abstract/Summary

The E3 ubiquitin ligase c-Cbl ubiquitinates the G protein-coupled receptor protease-activated receptor 2 (PAR(2)), which is required for postendocytic sorting of activated receptors to lysosomes, where degradation terminates signaling. The mechanisms of PAR(2) deubiquitination and its importance in trafficking and signaling of endocytosed PAR(2) are unknown. We report that receptor deubiquitination occurs between early endosomes and lysosomes and involves the endosomal deubiquitinating proteases AMSH and UBPY. Expression of the catalytically inactive mutants, AMSH(D348A) and UBPY(C786S), caused an increase in PAR(2) ubiquitination and trapped the receptor in early endosomes, thereby preventing lysosomal trafficking and degradation. Small interfering RNA knockdown of AMSH or UBPY also impaired deubiquitination, lysosomal trafficking, and degradation of PAR(2). Trapping PAR(2) in endosomes through expression of AMSH(D348A) or UBPY(C786S) did not prolong the association of PAR(2) with beta-arrestin2 or the duration of PAR(2)-induced ERK2 activation. Thus, AMSH and UBPY are essential for trafficking and down-regulation of PAR(2) but not for regulating PAR(2) dissociation from beta-arrestin2 or PAR(2)-mediated ERK2 activation.

Item Type:Article
Refereed:Yes
Divisions:No Reading authors. Back catalogue items
ID Code:30257
Uncontrolled Keywords:Animals Arrestins/metabolism Cell Line *Down-Regulation Endocytosis/physiology Endopeptidases/genetics/*metabolism Endosomal Sorting Complexes Required for Transport Endosomes/*enzymology Enzyme Activation Humans Lysosomes/metabolism Mitogen-Activated Protein Kinase 1/genetics/metabolism Pancreatic Elastase/metabolism Protein Transport/physiology RNA, Small Interfering/genetics/metabolism Receptor, PAR-2/genetics/*metabolism Recombinant Fusion Proteins/genetics/metabolism Trypsin/metabolism Ubiquitin Thiolesterase/genetics/*metabolism *Ubiquitination
Additional Information:Full text freely available via PUBMED link in Related URLs. Hasdemir, Burcu Murphy, Jane E Cottrell, Graeme S Bunnett, Nigel W DK39957/DK/NIDDK NIH HHS/ DK43207/DK/NIDDK NIH HHS/ DK57480/DK/NIDDK NIH HHS/ J Biol Chem. 2009 Oct 9;284(41):28453-66. Epub 2009 Aug 14.
Publisher:American Society for Biochemistry and Molecular Biology

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