Calpain-mediated proteolysis of polycystin-1 C-terminus induces JAK2 and ERK signal alterations |
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| Authors: | Hyunho Kim Ah-Young Kang Ah-ra Ko Hayne Cho Park Insuk So Jong Hoon Park Hae Il Cheong Young-Hwan Hwang Curie Ahn |
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| Institution: | 1. Transplantation Research Institute, Seoul National University Medical Research Center, Seoul, Republic of Korea;2. Department of Medicine, University of Maryland, Baltimore, MD, USA;3. Department of Medicine, Program of Immunology, Graduate School, Seoul National University, Seoul, Republic of Korea;4. Clinical Research Center, Samsung Biomedical Research Institute, Seoul, Republic of Korea;5. Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Republic of Korea;6. Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea;g Department of Biological Science, Sookmyung Women’s University, Seoul, Republic of Korea;h Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Republic of Korea;i Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea;j Department of Internal Medicine, Eulji General Hospital, Eulji University College of Medicine, Seoul, Republic of Korea;k Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea |
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| Abstract: | Autosomal dominant polycystic kidney disease (ADPKD), a hereditary renal disease caused by mutations in PKD1 (85%) or PKD2 (15%), is characterized by the development of gradually enlarging multiple renal cysts and progressive renal failure. Polycystin-1 (PC1), PKD1 gene product, is an integral membrane glycoprotein which regulates a number of different biological processes including cell proliferation, apoptosis, cell polarity, and tubulogenesis. PC1 is a target of various proteolytic cleavages and proteosomal degradations, but its role in intracellular signaling pathways remains poorly understood. Herein, we demonstrated that PC1 is a novel substrate for μ- and m-calpains, which are calcium-dependent cysteine proteases. Overexpression of PC1 altered both Janus-activated kinase 2 (JAK2) and extracellular signal-regulated kinase (ERK) signals, which were independently regulated by calpain-mediated PC1 degradation. They suggest that the PC1 function on JAK2 and ERK signaling pathways might be regulated by calpains in response to the changes in intracellular calcium concentration. |
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