Skip to main content
SpringerLink
Log in

DUSP13B/TMDP inhibits stress-activated MAPKs and suppresses AP-1-dependent gene expression

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The dual-specificity phosphatase (DUSP) 13 gene encodes two atypical DUSPs, DUSP13B/TMDP and DUSP13A/MDSP using alternative exons. DUSP13B protein is most highly expressed in testis, particularly in spermatocytes and round spermatids of the seminiferous tubules, while that of DUSP13A is restricted to skeletal muscle. Here, we show that DUSP13B inactivated MAPK activation in the order of selectivity, JNK = p38>ERK in cells, while DUSP13A did not show MAPK phosphatase activity. Reporter gene analysis showed that DUSP13B had significant inhibitory effect on AP-1-dependent gene expression, but DUSP13A did not. To our knowledge, DUSP13B is the first identified testis-specific phosphatase that inhibits stress-activated MAPKs. These data suggest an important role for DUSP13B in protection from external stress during spermatogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

DUSP:

Dual-specificity phosphatase

TMDP:

Testis- and skeletal muscle-specific DUSP

MDSP:

Muscle-restricted DUSP

MAP:

Mitogen-activated protein

MAPK:

MAP kinase

ERK:

Extracellular signal-regulated kinase

JNK:

c-Jun N-terminal kinase

AP-1:

Activating protein 1

SRE:

Serum responsive element

Luc:

Luciferase

SEK1:

SAPK/ERK kinase 1

MKK3:

MAPK kinase 3

GST:

Glutathione S-transferase

MKP:

MAP kinase phosphatase

VHR:

VH1-related

HA:

Hemagglutinin

PBS:

Phosphate-buffered saline

PMA:

12-O-tetradecanoylphorbol-13-acetate

DAPI:

4′,6-diamidino-2-phenylindole

pNPP:

P-nitrophenyl phosphate

References

  1. Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T (2004) Protein tyrosine phosphatases in the human genome. Cell 117(6):699–711

    Article  PubMed  CAS  Google Scholar 

  2. Patterson KI, Brummer T, O’Brien PM, Daly RJ (2009) Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J 418(2):475–489

    PubMed  CAS  Google Scholar 

  3. Todd JL, Tanner KG, Denu JM (1999) Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway. J Biol Chem 274(19):13271–13280

    Article  PubMed  CAS  Google Scholar 

  4. Todd JL, Rigas JD, Rafty LA, Denu JM (2002) Dual-specificity protein tyrosine phosphatase VHR down-regulates c-Jun N-terminal kinase (JNK). Oncogene 21(16):2573–2583

    Article  PubMed  CAS  Google Scholar 

  5. Schumacher MA, Todd JL, Rice AE, Tanner KG, Denu JM (2002) Structural basis for the recognition of a bisphosphorylated MAP kinase peptide by human VHR protein phosphatase. Biochemistry 41(9):3009–3017

    Article  PubMed  CAS  Google Scholar 

  6. Rahmouni S, Cerignoli F, Alonso A, Tsutji T, Henkens H, Zhu C, Louis-dit-Sully C, Moutschen M, Jiang W, Mustelin T (2006) Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence. Nat Cell Biol 8(5):524–531

    Article  PubMed  CAS  Google Scholar 

  7. Masuda K, Shima H, Katagiri C, Kikuchi K (2003) Activation of ERK induces phosphorylation of MAPK phosphatase-7, a JNK specific phosphatase, at Ser-446. J Biol Chem 278(34):32448–32456

    Article  PubMed  CAS  Google Scholar 

  8. Barsyte-Lovejoy D, Galanis A, Sharrocks AD (2002) Specificity determinants in MAPK signaling to transcription factors. J Biol Chem 277(12):9896–9903

    Article  PubMed  CAS  Google Scholar 

  9. Yang SH, Whitmarsh AJ, Davis RJ, Sharrocks AD (1998) Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1. EMBO J 17(6):1740–1749

    Article  PubMed  CAS  Google Scholar 

  10. Yang SH, Yates PR, Whitmarsh AJ, Davis RJ, Sharrocks AD (1998) The Elk-1 ETS-domain transcription factor contains a mitogen-activated protein kinase targeting motif. Mol Cell Biol 18(2):710–720

    PubMed  CAS  Google Scholar 

  11. Bogoyevitch MA, Kobe B (2006) Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases. Microbiol Mol Biol Rev 70(4):1061–1095

    Article  PubMed  CAS  Google Scholar 

  12. Nakamura K, Shima H, Watanabe M, Haneji T, Kikuchi K (1999) Molecular cloning and characterization of a novel dual-specificity protein phosphatase possibly involved in spermatogenesis. Biochem J 344:819–825

    Article  PubMed  CAS  Google Scholar 

  13. Chen HH, Luche R, Wei B, Tonks NK (2004) Characterization of two distinct dual specificity phosphatases encoded in alternative open reading frames of a single gene located on human chromosome 10q22.2. J Biol Chem 279(40):41404–41413

    Article  PubMed  CAS  Google Scholar 

  14. Park JE, Park BC, Kim HA, Song M, Park SG, Lee DH, Kim HJ, Choi HK, Kim JT, Cho S (2010) Positive regulation of apoptosis signal-regulating kinase 1 by dual-specificity phosphatase 13A. Cell Mol Life Sci 67(15):2619–2629

    Article  PubMed  CAS  Google Scholar 

  15. Katagiri C, Masuda K, Urano T, Yamashita K, Araki Y, Kikuchi K, Shima H (2005) Phosphorylation of Ser-446 determines stability of MKP-7. J Biol Chem 280(15):14716–14722

    Article  PubMed  CAS  Google Scholar 

  16. Takagaki K, Satoh T, Tanuma N, Masuda K, Takekawa M, Shima H, Kikuchi K (2004) Characterization of a novel low-molecular-mass dual-specificity phosphatase-3 (LDP-3) that enhances activation of JNK and p38. Biochem J 383:447–455

    Article  PubMed  CAS  Google Scholar 

  17. Masuda K, Shima H, Watanabe M, Kikuchi K (2001) MKP-7, a novel mitogen-activated protein kinase phosphatase, functions as a shuttle protein. J Biol Chem 276(42):39002–39011

    Article  PubMed  CAS  Google Scholar 

  18. Koda T, Hasan S, Sasaki A, Arimura Y, Kakinuma M (1994) Regulatory sequences required for hst-1 expression in embryonal carcinoma cells. FEBS Lett 342(1):71–75

    Article  PubMed  CAS  Google Scholar 

  19. Masuda K, Katagiri C, Nomura M, Sato M, Kakumoto K, Akagi T, Kikuchi K, Tanuma N, Shima H (2010) MKP-7, a JNK phosphatase, blocks ERK-dependent gene activation by anchoring phosphorylated ERK in the cytoplasm. Biochem Biophys Res Commun 393(2):201–206

    Article  PubMed  CAS  Google Scholar 

  20. Nakamura K, Tanoue K, Satoh T, Takekawa M, Watanabe M, Shima H, Kikuchi K (2002) A novel low-molecular-mass dual-specificity phosphatase, LDP-2, with a naturally occurring substitution that affects substrate specificity. J Biochem 132(3):463–470

    PubMed  CAS  Google Scholar 

  21. Owens DM, Keyse SM (2007) Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26(22):3203–3213

    Article  PubMed  CAS  Google Scholar 

  22. Kim SJ, Jeong DG, Yoon TS, Son JH, Cho SK, Ryu SE, Kim JH (2007) Crystal structure of human TMDP, a testis-specific dual specificity protein phosphatase: implications for substrate specificity. Proteins 66(1):239–245

    Article  PubMed  CAS  Google Scholar 

  23. Yuvaniyama J, Denu JM, Dixon JE, Saper MA (1996) Crystal structure of the dual specificity protein phosphatase VHR. Science 272(5266):1328–1331

    Article  PubMed  CAS  Google Scholar 

  24. Kim WY, Sharpless NE (2006) The regulation of INK4/ARF in cancer and aging. Cell 127(2):265–275

    Article  PubMed  CAS  Google Scholar 

  25. Van de Peer Y, Maere S, Meyer A (2009) The evolutionary significance of ancient genome duplications. Nat Rev Genet 10(10):725–732

    Article  PubMed  Google Scholar 

  26. Iwanaga A, Wang G, Gantulga D, Sato T, Baljinnyam T, Shimizu K, Takumi K, Hayashi M, Akashi T, Fuse H, Sugihara K, Asano M, Yoshioka K (2008) Ablation of the scaffold protein JLP causes reduced fertility in male mice. Transgenic Res 17(6):1045–1058

    Article  PubMed  CAS  Google Scholar 

  27. Matthews CP, Colburn NH, Young MR (2007) AP-1 a target for cancer prevention. Curr Cancer Drug Targets 7(4):317–324

    Article  PubMed  CAS  Google Scholar 

  28. Suomalainen L, Dunkel L, Ketola I, Eriksson M, Erkkilä K, Oksjoki R, Taari K, Heikinheimo M, Pentikäinen V (2004) Activator protein-1 in human male germ cell apoptosis. Mol Hum Reprod 10(10):743–753

    Article  PubMed  CAS  Google Scholar 

  29. Shalini S, Bansal MP (2006) Role of selenium in spermatogenesis: differential expression of cjun and cfos in tubular cells of mice testis. Mol Cell Biochem 292(1–2):27–38

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. J. Magae (Institute of Research and Innovation, Kashiwa, Japan) and N.H. Heintz (University of Vermont, Burlington, VT) for providing us with pCMV-β-galactosidase. We thank Dr. M. Karin (University of California, San Diego) for pSRα-HA-ERK2. We thank Dr. M. Takekawa (Nagoya University) for pEBG-SEK1 and pEBG-MKK3. We thank Dr. T. Koda (Hokkaido University) for the anti-GST antibody. Thanks are also due to N. Sasaki for secretarial assistance. This work was supported in part by grants-in-aid for Scientific Research provided by the Japan Society for the Promotion of Science (to H.S., Y.Y., K.S., N.T., and M.S.).

Author information

Author notes

  1. Chiaki Katagiri

    Present address: Molecular and Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan

Authors and Affiliations

  1. Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Medeshima-Shiode, Natori, 981-1293, Japan

    Chiaki Katagiri, Kouhei Masuda, Miyuki Nomura, Yoji Yamashita, Ryuichi Katakura, Ken-ichi Shiiba, Eiki Nomura, Masami Sato, Nobuhiro Tanuma & Hiroshi Shima

  2. Division of Biochemical Oncology and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    Chiaki Katagiri, Kouhei Masuda, Kan Tanoue & Shoko Fujita

  3. Division of Cancer Molecular Biology, Tohoku University School of Medicine, Natori, Japan

    Nobuhiro Tanuma & Hiroshi Shima

Authors
  1. Chiaki Katagiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kouhei Masuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miyuki Nomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kan Tanoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shoko Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoji Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ryuichi Katakura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ken-ichi Shiiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eiki Nomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masami Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nobuhiro Tanuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hiroshi Shima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroshi Shima.

Additional information

Chiaki Katagiri and Kouhei Masuda contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Katagiri, C., Masuda, K., Nomura, M. et al. DUSP13B/TMDP inhibits stress-activated MAPKs and suppresses AP-1-dependent gene expression. Mol Cell Biochem 352, 155–162 (2011). https://doi.org/10.1007/s11010-011-0749-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-0749-x

Keywords

Search

Navigation