title: Evidence that TMEM67 causes polycystic kidney disease through activation of JNK/ERK-dependent pathways.
abstract: TMEM67 mutations are associated with severe autosomal recessive polycystic kidney disease (ARPKD) in both humans and animals. However, the molecular mechanisms underlying the pathogenesis of PKD caused by TMEM67 mutations remain to be determined. We have investigated the possible signalling pathways involved in the pathogenesis of PKD. Overexpression of TMEM67 in human embryonic kidney (HEK293) cells triggered the activation of overall tyrosine phosphorylated proteins, extracellular signal-regulated kinase (ERK) and c-jun N-terminal KINASE (JNK). Activation was suppressed by pharmacological inhibitors of ERK or JNK. Activation of the mammalian target of rapamycin (mTOR) or p70s kinase (S6K) did not occur, although elevated phosphorylation of eIF4E-binding protein 1 (4E-BP1), a target of S6K, was seen. In animal studies, activation of a variety of signalling molecules was linked to ERK, JNK and 4E-BP1. Significant induction of phosphorylation of tyrosine phosphorylated proteins, ERK and 4E-BP1, at different postnatal ages was detected in mutant kidneys of B6C3Fe a/a-bpck mice, a cystic renal disease mouse model caused by TMEM67 loss of function mutation. Based on these in vitro and in vivo observations, we propose that TMEM67 mutations cause PKD through ERK- and JNK-dependent signalling pathways, which may provide novel insight into the therapy of polycystic kidney diseases.
authors: Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China, 300211.
authors: E
authors: E
authors: Du
authors: Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, Kentucky 40292.
authors: Hong
authors: H
authors: Li
authors: Department of Medicine, School of Medicine, University of Louisville, Louisville, Kentucky 40292.
authors: Shunying
authors: S
authors: Jin
authors: Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, Kentucky 40292.
authors: Xuemei
authors: X
authors: Hu
authors: Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, Kentucky 40292.
authors: Mengsheng
authors: M
authors: Qiu
authors: Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China, 300211.
authors: Ruifa
authors: R
authors: Han
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D007690:Polycystic Kidney Diseases / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; C583064:TMEM67 protein, mouse; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases