Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinases and juxtamembrane region.
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. 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.
Zhang
Zhiwei
Z
Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, and Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts, USA.
Humphreys
Benjamin D
BD
Bonventre
Joseph V
JV
D000818:Animals; D000975:Antioxidants; D015415:Biomarkers / Q000378:metabolism; D019556:COS Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004151:Dipeptides; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000652:urine; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010663:Phenylmercury Compounds; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011759:Pyrrolidines; D011991:Receptors, Virus / Q000378:metabolism*; D013859:Thiocarbamates; D014638:Vanadates
D000975:Antioxidants; D015415:Biomarkers; D004151:Dipeptides; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D010663:Phenylmercury Compounds; D020033:Protein Isoforms; D011759:Pyrrolidines; D011991:Receptors, Virus; D013859:Thiocarbamates; C076715:pervanadate; C020972:pyrrolidine dithiocarbamic acid; D014638:Vanadates; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; D008666:Metalloendopeptidases