The DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth

Hyunjoo Kim, Ho-June Lee, Yumin Oh, Seon-Guk Choi, Se-Hoon Hong, Hyo-Jin Kim, Song-Yi Lee, Ji-Woo Choi, Deog Su Hwang, Key-Sun Kim, Hyo-Joon Kim, Jianke Zhang, Hyun-Jo Youn, Dong-Young Noh and Yong-Keun Jung ()
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Hyunjoo Kim: School of Biological Science/Bio-Max Institute, Seoul National University
Ho-June Lee: Genentech, Inc. 1 DNA Way
Yumin Oh: School of Biological Science/Bio-Max Institute, Seoul National University
Seon-Guk Choi: School of Biological Science/Bio-Max Institute, Seoul National University
Se-Hoon Hong: School of Biological Science/Bio-Max Institute, Seoul National University
Hyo-Jin Kim: Genentech, Inc. 1 DNA Way
Song-Yi Lee: School of Biological Science/Bio-Max Institute, Seoul National University
Ji-Woo Choi: Center for Neuroscience, Korea Institute of Science and Technology
Deog Su Hwang: School of Biological Science/Bio-Max Institute, Seoul National University
Key-Sun Kim: Center for Neuroscience, Korea Institute of Science and Technology
Hyo-Joon Kim: Hanyang University
Jianke Zhang: Thomas Jefferson University
Hyun-Jo Youn: Chonbuk National University Medical School
Dong-Young Noh: Seoul National University College of Medicine
Yong-Keun Jung: School of Biological Science/Bio-Max Institute, Seoul National University

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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-FADDSer194. 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-FADDSer191. 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.

Date: 2014
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DOI: 10.1038/ncomms4351

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