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; Yong Keun Jung

doi:10.1038/ncomms4351

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, Yong Keun Jung

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

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.

Original language	English (US)
Article number	3351
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4351
State	Published - Feb 19 2014
Externally published	Yes

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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@article{637acb24abc24c6786d85d66976db580,

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.",

author = "Hyunjoo Kim and Lee, {Ho June} and Yumin Oh and Choi, {Seon Guk} and Hong, {Se Hoon} and Kim, {Hyo Jin} and Lee, {Song Yi} and Choi, {Ji Woo} and {Su Hwang}, Deog and Kim, {Key Sun} and Kim, {Hyo Joon} and Jianke Zhang and Youn, {Hyun Jo} and Noh, {Dong Young} and Jung, {Yong Keun}",

note = "Funding Information: H.-J.K. and H.-J.L. were supported in part by a National Research Foundation of Korea Grant funded by the Korean Government (C00031) and by the BK21 programme, respectively. K.-S.K. was supported by Korea Institute of Science and Technology (KIST) R&D institutional programme. This work was supported by the grants from the Global Research Laboratory programme (National Research Foundation (NRF)-2010-00341) and Basic Atomic Energy Research Institute (BAERI) (2012-00004864), and by the KIST (2E24090-13-060) funded by the Ministry of Education, Science and Technology (MEST). Funding Information: Human cancer tissue analysis. The biospecimens for this study were provided by the Biobank of Chonbuk National University Hospital, a member of the National Biobank of Korea, which is supported by the Ministry of Health, Welfare and Family Affairs. All samples derived from the National Biobank of Korea were obtained with informed consent under institutional review board-approved protocols.",

year = "2014",

month = feb,

day = "19",

doi = "10.1038/ncomms4351",

language = "English (US)",

volume = "5",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - The DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth

AU - Kim, Hyunjoo

AU - Lee, Ho June

AU - Oh, Yumin

AU - Choi, Seon Guk

AU - Hong, Se Hoon

AU - Kim, Hyo Jin

AU - Lee, Song Yi

AU - Choi, Ji Woo

AU - Su Hwang, Deog

AU - Kim, Key Sun

AU - Kim, Hyo Joon

AU - Zhang, Jianke

AU - Youn, Hyun Jo

AU - Noh, Dong Young

AU - Jung, Yong Keun

N1 - Funding Information: H.-J.K. and H.-J.L. were supported in part by a National Research Foundation of Korea Grant funded by the Korean Government (C00031) and by the BK21 programme, respectively. K.-S.K. was supported by Korea Institute of Science and Technology (KIST) R&D institutional programme. This work was supported by the grants from the Global Research Laboratory programme (National Research Foundation (NRF)-2010-00341) and Basic Atomic Energy Research Institute (BAERI) (2012-00004864), and by the KIST (2E24090-13-060) funded by the Ministry of Education, Science and Technology (MEST). Funding Information: Human cancer tissue analysis. The biospecimens for this study were provided by the Biobank of Chonbuk National University Hospital, a member of the National Biobank of Korea, which is supported by the Ministry of Health, Welfare and Family Affairs. All samples derived from the National Biobank of Korea were obtained with informed consent under institutional review board-approved protocols.

PY - 2014/2/19

Y1 - 2014/2/19

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms4351

DO - 10.1038/ncomms4351

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C2 - 24548998

AN - SCOPUS:84894597311

SN - 2041-1723

VL - 5

JO - Nature communications

JF - Nature communications

M1 - 3351

ER -

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

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