TY - JOUR
T1 - Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinases and juxtamembrane region
AU - Zhang, Zhiwei
AU - Humphreys, Benjamin D.
AU - Bonventre, Joseph V.
PY - 2007/10
Y1 - 2007/10
N2 - Kidney injury molecule-1 (KIM-1) is markedly upregulated in renal proximal tubule cells by stimuli that promote dedifferentiation, including ischemic or toxic injury, as well as in cases of tubulointerstitial disease, polycystic kidney disease, and renal cell carcinoma. Structurally, KIM-1 possesses a single transmembrane domain and undergoes membrane-proximal cleavage, which leads to the release of soluble KIM-1 ectodomain into the urine. The abstract for this article has been revised by the editorial office; please review and approve or correct as needed. Urinary KIM-1 ectodomain is a promising sensitive and specific biomarker for acute kidney injury in humans, and therefore it is important to determine what regulates KIM-1 shedding. We found that constitutive cleavage of KIM-1 is mediated by ERK activation, and that cleavage is accelerated by p38 MAP kinase activation. After cleavage, a 14-kD membrane-bound fragment of KIM-1, which contains two highly conserved tyrosine residues, was tyrosine-phosphorylated. Mutagenesis studies demonstrated that the juxtamembrane secondary structure, not the primary amino acid sequence, was critical to the cleavage of KIM-1.
AB - Kidney injury molecule-1 (KIM-1) is markedly upregulated in renal proximal tubule cells by stimuli that promote dedifferentiation, including ischemic or toxic injury, as well as in cases of tubulointerstitial disease, polycystic kidney disease, and renal cell carcinoma. Structurally, KIM-1 possesses a single transmembrane domain and undergoes membrane-proximal cleavage, which leads to the release of soluble KIM-1 ectodomain into the urine. The abstract for this article has been revised by the editorial office; please review and approve or correct as needed. Urinary KIM-1 ectodomain is a promising sensitive and specific biomarker for acute kidney injury in humans, and therefore it is important to determine what regulates KIM-1 shedding. We found that constitutive cleavage of KIM-1 is mediated by ERK activation, and that cleavage is accelerated by p38 MAP kinase activation. After cleavage, a 14-kD membrane-bound fragment of KIM-1, which contains two highly conserved tyrosine residues, was tyrosine-phosphorylated. Mutagenesis studies demonstrated that the juxtamembrane secondary structure, not the primary amino acid sequence, was critical to the cleavage of KIM-1.
UR - http://www.scopus.com/inward/record.url?scp=34948814501&partnerID=8YFLogxK
U2 - 10.1681/ASN.2007030325
DO - 10.1681/ASN.2007030325
M3 - Article
C2 - 17898236
AN - SCOPUS:34948814501
SN - 1046-6673
VL - 18
SP - 2704
EP - 2714
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 10
ER -