title: Scaffold Role of DUSP22 in ASK1-MKK7-JNK Signaling Pathway.
abstract: Mitogen-activated protein kinases (MAPKs) are involved in a variety of intracellular events such as gene expression, cell proliferation, and programmed cell death. MAPKs are activated by dual phosphorylation on threonine and tyrosine residues through sequential activation of protein kinases. Recent studies have shown that the protein kinases involved in MAPK signal transductions might be organized into signaling complexes by scaffold proteins. These scaffold proteins are essential regulators that function by assembling the relevant molecular components in mammalian cells. In this study, we report that dual-specificity phosphatase 22 (DUSP22), a member of the protein tyrosine phosphatase family, acts as a distinct scaffold protein in c-Jun N-terminal kinase (JNK) signaling. DUSP22 increased the phosphorylation in the activation loop of JNK regardless of its phosphatase activity but had no effect on phosphorylation levels of ERK and p38 in mammalian cells. Furthermore, DUSP22 selectively associated with apoptosis signal-regulating kinase 1 (ASK1), MAPK kinase 7 (MKK7), and JNK1/2. Both JNK phosphorylation and JNK-mediated apoptosis increased in a concentration-dependent manner regardless of DUSP22 phosphatase activity at low DUSP22 concentrations, but then decreased at higher DUSP22 concentrations, which is the prominent feature of a scaffold protein. Thus, our data suggest that DUSP22 regulates cell death by acting as a scaffold protein for the ASK1-MKK7-JNK signal transduction pathway independently of its phosphatase activity.
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
authors.forename: Anna
authors.initials: A
authors.lastname: Ju
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
authors.forename: Young-Chang
authors.initials: YC
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
authors.forename: Ba Reum
authors.initials: BR
authors.lastname: Kim
authors.affiliation: Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
authors.forename: Sung Goo
authors.initials: SG
authors.lastname: Park
authors.affiliation: Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute for Drug Development, Chonnam National University, Gwangju, 61186, Republic of Korea.
authors.forename: Kwonseop
authors.initials: K
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
authors.forename: Jaehwi
authors.initials: J
authors.lastname: Lee
authors.affiliation: Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Park
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
authors.forename: Sayeon
authors.initials: S
authors.lastname: Cho
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048688:MAP Kinase Kinase 7 / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding
chemical_list: D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; C442824:DUSP22 protein, human; D054637:Dual-Specificity Phosphatases; D053148:Caspase 3