title: Zinc finger protein ZPR9 functions as an activator of AMPK-related serine/threonine kinase MPK38/MELK involved in ASK1/TGF-β/p53 signaling pathways.
abstract: Murine protein serine-threonine kinase 38 (MPK38), an AMP-activated protein kinase (AMPK)-related kinase, has been implicated in the induction of apoptosis signal-regulating kinase 1 (ASK1)-, transforming growth factor-β (TGF-β)-, and p53-mediated activity involved in metabolic homeostasis. Here, zinc finger protein ZPR9 was found to be an activator of MPK38. The association of MPK38 and ZPR9 was mediated by cysteine residues present in each of these two proteins, Cys269and Cys286of MPK38 and Cys305and Cys308of ZPR9. MPK38 phosphorylated ZPR9 at Thr252. Wild-type ZPR9, but not the ZPR9 mutant T252A, enhanced ASK1, TGF-β, and p53 function by stabilizing MPK38. The requirement of ZPR9 Thr252phosphorylation was validated using CRISPR/Cas9-mediated ZPR9 (T252A) knockin cell lines. The knockdown of endogenous ZPR9 showed an opposite trend, resulting in the inhibition of MPK38-dependent ASK1, TGF-β, and p53 function. This effect was also demonstrated in mouse embryonic fibroblast (MEF) cells that were haploinsufficient (+/-) for ZPR9, NIH 3T3 cells with inducible knockdown of ZPR9, and CRISPR/Cas9-mediated ZPR9 knockout cells. Furthermore, high-fat diet (HFD)-fed mice displayed reduced MPK38 kinase activity and ZPR9 expression compared to that in mice on control chow, suggesting that ZPR9 acts as a physiological activator of MPK38 that may participate in obesity.
authors.affiliation: Department of Biochemistry, School of Biological Sciences, Chungbuk National University, Cheongju 28644, Republic of Korea.
authors.forename: Hyun-A
authors.initials: HA
authors.lastname: Seong
authors.affiliation: National Center for Nanoscience and Nanotechnology, University of Madras, Guindy Campus, Chennai 600025, India.
authors.forename: Ravi
authors.initials: R
authors.lastname: Manoharan
authors.affiliation: Department of Biochemistry, School of Biological Sciences, Chungbuk National University, Cheongju 28644, Republic of Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Ha
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D010084:Oxidation-Reduction; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C448990:ZNF622 protein, human; D006861:Hydrogen Peroxide; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D055372:AMP-Activated Protein Kinases