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Title: Calpain-mediated proteolysis of polycystin-1 C-terminus induces JAK2 and ERK signal alterations

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. - Highlights: • Polycystin-1 is a target of ubiquitin-independent degradation by calpains. • The PEST domain is required for calpain-mediated degradation of polycystin-1. • Polycystin-1 may independently regulate JAK2 and ERK signaling pathways.
Authors:
 [1] ;  [2] ;  [1] ;  [3] ;  [4] ;  [1] ;  [3] ;  [5] ;  [6] ;  [7] ;  [3] ;  [3] ;  [7] ;  [3] ;
  1. Transplantation Research Institute, Seoul National University Medical Research Center, Seoul (Korea, Republic of)
  2. (United States)
  3. (Korea, Republic of)
  4. Clinical Research Center, Samsung Biomedical Research Institute, Seoul (Korea, Republic of)
  5. Department of Physiology, Seoul National University College of Medicine, Seoul (Korea, Republic of)
  6. Department of Biological Science, Sookmyung Women’s University, Seoul (Korea, Republic of)
  7. Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul (Korea, Republic of)
Publication Date:
OSTI Identifier:
22278242
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 320; Journal Issue: 1; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CALCIUM; CELL PROLIFERATION; CYSTEINE; DISEASES; GLYCOPROTEINS; KIDNEYS; PROTEOLYSIS; RECEPTORS; SIGNALS