title: The DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth.
abstract: Adenylate kinase 2 (AK2), which balances adenine nucleotide pool, is a multi-functional protein. Here we show that AK2 negatively regulates tumour cell growth. AK2 forms a complex with dual-specificity phosphatase 26 (DUSP26) phosphatase and stimulates DUSP26 activity independently of its AK activity. AK2/DUSP26 phosphatase protein complex dephosphorylates fas-associated protein with death domain (FADD) and regulates cell growth. AK2 deficiency enhances cell proliferation and induces tumour formation in a xenograft assay. This anti-growth function of AK2 is associated with its DUSP26-stimulating activity. Downregulation of AK2 is frequently found in tumour cells and human cancer tissues showing high levels of phospho-FADD(Ser194). Moreover, reconstitution of AK2 in AK2-deficient tumour cells retards both cell proliferation and tumourigenesis. Consistent with this, AK2(+/-) mouse embryo fibroblasts exhibit enhanced cell proliferation with a significant alteration in phospho-FADD(Ser191). These results suggest that AK2 is an associated activator of DUSP26 and suppresses cell proliferation by FADD dephosphorylation, postulating AK2 as a negative regulator of tumour growth.
authors.affiliation: 1] School of Biological Science/Bio-Max Institute, Seoul National University, Gwanak-gu, Seoul 151-747, Korea [2].
authors.forename: Hyunjoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: 1] Department of Discovery Oncology, Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA [2].
authors.forename: Ho-June
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: School of Biological Science/Bio-Max Institute, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Oh
authors.affiliation: School of Biological Science/Bio-Max Institute, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Seon-Guk
authors.initials: SG
authors.lastname: Choi
authors.affiliation: School of Biological Science/Bio-Max Institute, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Department of Discovery Oncology, Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: School of Biological Science/Bio-Max Institute, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Song-Yi
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Center for Neuroscience, Korea Institute of Science and Technology, Seoul 136-791, Korea.
authors.forename: Ji-Woo
authors.initials: JW
authors.lastname: Choi
authors.affiliation: School of Biological Science/Bio-Max Institute, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Deog
authors.initials: D
authors.lastname: Su Hwang
authors.affiliation: Center for Neuroscience, Korea Institute of Science and Technology, Seoul 136-791, Korea.
authors.forename: Key-Sun
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Hanyang University, Ansan, Kyeonggi-do 425-791, Korea.
authors.forename: Hyo-Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Jianke
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Chonbuk National University Medical School, Jeonju 561-180, Korea.
authors.forename: Hyun-Jo
authors.initials: HJ
authors.lastname: Youn
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Seoul 110-744, Korea.
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Noh
authors.affiliation: School of Biological Science/Bio-Max Institute, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D053719:Tandem Mass Spectrometry; D023041:Xenograft Model Antitumor Assays
chemical_list: C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D000263:Adenylate Kinase; C110938:adenylate kinase 2; D054639:Mitogen-Activated Protein Kinase Phosphatases; C500883:DUSP26 protein, human; D054637:Dual-Specificity Phosphatases