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Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) mediates post-endocytic trafficking of protease-activated receptor 2 and calcitonin receptor-like receptor

Hasdemir, B., Bunnett, N. W. and Cottrell, G. S. ORCID: (2007) Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) mediates post-endocytic trafficking of protease-activated receptor 2 and calcitonin receptor-like receptor. The Journal of Biological Chemistry, 282 (40). pp. 29646-57. ISSN 1083-351X

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To link to this item DOI: 10.1074/jbc.M702974200


The E3 ligase c-Cbl ubiquitinates protease-activated receptor 2 (PAR(2)), which is required for post-endocytic sorting of PAR(2) to lysosomes, where degradation arrests signaling. The mechanisms of post-endocytic sorting of ubiquitinated receptors are incompletely understood. Here, we investigated the role of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), in post-endocytic sorting and signaling of PAR(2). In HEK-PAR(2) cells, PAR(2) activating peptide (PAR(2)-AP) induced PAR(2) trafficking from the cell surface to early endosomes containing endogenous HRS, and then to lysosomes. HRS overexpression or knockdown with small interfering RNA caused formation of enlarged HRS-positive endosomes, where activated PAR(2) and c-Cbl accumulated, and PAR(2) failed to traffic to lysosomes. Overexpression of HRS prevented PAR(2)-AP-induced degradation of PAR(2), as determined by Western blotting. Overexpression of HRS mutant lacking an ubiquitin-binding motif similarly caused retention of PAR(2) in enlarged endosomes. Moreover, HRS overexpression or knockdown caused retention of ubiquitin-resistant PAR(2)Delta14K/R in enlarged HRS-containing endosomes, preventing recycling and resensitization of PAR(2)Delta14K/R. HRS overexpression or knockdown similarly prevented lysosomal trafficking and recycling of calcitonin receptor-like receptor, a non-ubiquitinated receptor that traffics to lysosomes after sustained activation and recycles after transient activation. Thus, HRS plays a critically important role in the post-endocytic sorting of single receptors, PAR(2) and CLR, to both degradative and recycling pathways. This sorting role for HRS is independent of its ubiquitin-interacting motif, and it can regulate trafficking of both ubiquitinated and non-ubiquitinated PAR(2) and non-ubiquitinated CLR. The ultimate sorting decision to degradative or recycling pathways appears to occur downstream from HRS.

Item Type:Article
Divisions:Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
No Reading authors. Back catalogue items
ID Code:30268
Uncontrolled Keywords:Calcitonin Receptor-Like Protein Cell Line *Endocytosis Endosomal Sorting Complexes Required for Transport Endosomes/metabolism Gene Expression Regulation HeLa Cells Humans Microscopy, Confocal Phosphoproteins/*metabolism Plasmids/metabolism Proto-Oncogene Proteins c-cbl/metabolism RNA, Small Interfering/metabolism Receptor, PAR-2/*metabolism Receptors, Calcitonin/*metabolism Transfection Ubiquitin/metabolism
Additional Information:Hasdemir, Burcu Bunnett, Nigel W Cottrell, Graeme S DK39957/DK/NIDDK NIH HHS/ DK43207/DK/NIDDK NIH HHS/ DK57840/DK/NIDDK NIH HHS/ J Biol Chem. 2007 Oct 5;282(40):29646-57. Epub 2007 Aug 3.
Publisher:American Society for Biochemistry and Molecular Biology

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