Shedding of Kidney Injury Molecule-1, a Putative Adhesion Protein Involved in Renal Regeneration

KIM-1 (kidney injury molecule-1) is a type I transmembrane glycoprotein expressed on dedifferentiated renal proximal tubule epithelial cells undergoing regeneration after toxic or ischemic injury. The extracellular domain of KIM-1 is composed of an immunoglobulin-like domain topping a long mucin-lik...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-10, Vol.277 (42), p.39739-39748
Main Authors: Bailly, Veronique, Zhang, Zhiwei, Meier, Werner, Cate, Richard, Sanicola, Michele, Bonventre, Joseph V
Format: Article
Language:English
Subjects:
Alternative Splicing
Amino Acid Sequence
Animals
Antineoplastic Agents - pharmacology
Binding Sites
Biotinylation
Blotting, Western
Cell Adhesion
Cell Adhesion Molecules - chemistry
Cell Adhesion Molecules - metabolism
Cell Line
Cell Membrane - metabolism
COS Cells
Cytoplasm - metabolism
Dipeptides - pharmacology
Dose-Response Relationship, Drug
Enzyme-Linked Immunosorbent Assay
Epithelial Cells - metabolism
Flow Cytometry
Humans
Kidney - metabolism
Kidney - physiology
Membrane Proteins
Metalloendopeptidases - antagonists & inhibitors
Microscopy, Fluorescence
Molecular Sequence Data
Phenylalanine - analogs & derivatives
Phenylalanine - pharmacology
Precipitin Tests
Protease Inhibitors - pharmacology
Protein Binding
Protein Structure, Tertiary
Recombinant Proteins - metabolism
RNA, Messenger - metabolism
Thiophenes - pharmacology
Time Factors
Tissue Distribution
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Description
Summary:KIM-1 (kidney injury molecule-1) is a type I transmembrane glycoprotein expressed on dedifferentiated renal proximal tubule epithelial cells undergoing regeneration after toxic or ischemic injury. The extracellular domain of KIM-1 is composed of an immunoglobulin-like domain topping a long mucin-like domain, a structure that points to a possible role in cell adhesion by homology to several known adhesion proteins. Two splice variants (a and b), of the human KIM-1 having identical extracellular domains, differ in their cytoplasmic domains and tissue distributions. In this study, we report that the KIM-1b transcript is expressed predominantly in adult human kidney. We describe the generation of 10 monoclonal antibodies against the extracellular domain of human KIM-1, the mapping of their binding sites, and their use in identifying various forms of the protein. We show that human KIM-1b is expressed in adult kidney cell lines, and we demonstrate that a soluble form of KIM-1 is shed constitutively into the culture medium of the cell lines expressing endogenous or recombinant KIM-1b by membrane-proximal cleavage. A monoclonal antibody that binds at or close to the proteolytic site can partially block the shedding of KIM-1. Release of soluble KIM-1 is enhanced by activating the cells with phorbol 12-myristate 13-acetate and can be inhibited with two metalloproteinase inhibitors, BB-94 (Batimastat) and GM6001 (Ilomastat), suggesting that the cleavage is mediated by a metalloproteinase. We propose that the shedding of KIM-1 in the kidney undergoing regeneration constitutes an active mechanism allowing dedifferentiated regenerating cells to scatter on denuded patches of the basement membrane and reconstitute a continuous epithelial layer.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M200562200