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Publication : Ectodomain shedding and autocleavage of the cardiac membrane protease corin.

First Author  Jiang J Year  2011
Journal  J Biol Chem Volume  286
Issue  12 Pages  10066-72
PubMed ID  21288900 Mgi Jnum  J:170934
Mgi Id  MGI:4947910 Doi  10.1074/jbc.M110.185082
Citation  Jiang J, et al. (2011) Ectodomain shedding and autocleavage of the cardiac membrane protease corin. J Biol Chem 286(12):10066-72
abstractText  Corin is a cardiac membrane protease that activates natriuretic peptides. It is unknown how corin function is regulated. Recently, soluble corin was detected in human plasma, suggesting that corin may be shed from cardiomyocytes. Here we examined soluble corin production and activity and determined the proteolytic enzymes responsible for corin cleavage. We expressed human corin in HEK 293 cells and detected three soluble fragments of approximately 180, approximately 160, and approximately 100 kDa, respectively, in the cultured medium by Western blot analysis. All three fragments were derived from activated corin molecules. Similar results were obtained in HL-1 cardiomyocytes. Using protease inhibitors, ionomycin and phorbol myristate acetate stimulation, small interfering RNA knockdown, and site-directed mutagenesis, we found that ADAM10 was primarily responsible for shedding corin in its juxtamembrane region to release the approximately 180-kDa fragment, corresponding to the near-entire extracellular region. In contrast, the approximately 160- and approximately 100-kDa fragments were from corin autocleavage at Arg-164 in frizzled 1 domain and Arg-427 in LDL receptor 5 domain, respectively. In functional studies, the approximately 180-kDa fragment activated atrial natriuretic peptide, whereas the approximately 160- and approximately 100-kDa fragments did not. Our data indicate that ADAM-mediated shedding and corin autocleavage are important mechanisms regulating corin function and preventing excessive, potentially hazardous, proteolytic activities in the heart.
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