Phosphatase Subfamily DSP8

Phosphatase Classification: Superfamily CC1: Family DSP: Subfamily DSP8

DSP8 is a metazoan subfamily that functions as MKP with preference towards JNK and p38. It is single copy in invertebrate but two copies in most vertebrates. The two human members DUSP8 and DUSP16 have different tissue expression patterns.

Evolution

DSP8 is found in metazoan but absent from most arthropoda. It is typically single-copy in invertebrate, but expanded to two genes, DUSP8 and DUSP16 in vertebrates.

Domain Structure

The domain dissection is mainly based upon DUSP16 studies. But according to the sequence alignment and similarity, human DUSP8 has the same domain combination as DUSP16.

Human DUSP16 possesses a long C-terminal stretch containing a nuclear export signal (NES), two nuclear localization signal (NLS) and two PEST motifs, in addition to the rhodanese domain and the dual specificity phosphatase catalytic domain, both of which are conserved among MKP family members (see figure 9). The rhodanese domain is required for interaction with ERK and p38, whereas phosphatase domain is required for interaction with JNK and p38, which is likely to be important for DUSP16 to suppress JNK and p38 activations. The COOH-terminal stretch of DUSP16 was shown to determine JNK preference for MKP-7 by masking MKP-7 activity toward p38 and is a domain bound by ERK. [1].

DUSP16 also binds to JNK scaffolds, - JNK3 scaffold protein beta-arrestin 2 and JNK-interacting protein-1 (JIP-1), via 394-443 on C-terminal stretch [2, 3].

Functions

DUSP8

Human DUSP8 is a protein tyrosine phosphatase abundant in brain that inactivates mitogen-activated protein kinase. It is expressed predominantly in the adult brain, heart, and skeletal muscle. In addition, in situ hybridization histochemistry of mouse embryo revealed high levels of expression and a wide distribution in the central and peripheral nervous system [4] (tissue expression see GTEx).

DUSP16 (MKP7)

DUSP16 mainly functions in MAPK pathways. It is expressed in many different tissues and is highest expressed in adrenal gland (see GTEx).

DUSP16 is predominantly localized in the cytoplasm when expressed in cultured cells, whereas DUSP8 (hVH5) is both in the nucleus and the cytoplasm. Its localization became exclusively nuclear following leptomycin B treatment or introduction of a mutation in the nuclear export signal. DUSP16 binds to and inactivates p38 MAPK and JNK/SAPK, but not ERK. In particular, DUSP16 binds to and inactivates p38 alpha and -beta isoforms, but not gamma or delta. A mutant form DUSP16 functioned as a dominant negative particularly against the dephosphorylation of JNK, suggesting that DUSP16 works as a JNK-specific phosphatase in vivo [2, 5, 6]. Meanwhile, the structure of DUSP16 binding with p38alpha has been solved [7].

Although DUSP16 does not dephoshorylate ERK, it has been reported to bind to ERK [1]. It is phosphorylated at serine 446 by ERK, which stabilize DUSP16 (longer half life) and therefore blocks JNK activation [1, 8]. On another hand, DUSP16 functions as ERK scaffold, which down-regulates ERK-dependent gene expression by blocking nuclear accumulation of phospho-ERK [9].

DUSP16 can be nitrosylated and inactivated by chemokine stromal cell-derived factor-1alpha (SDF-1alpha), therefore inhibiting the activation of JNK and enhancing endothelial migration [10].

References

1. Masuda K, Shima H, Katagiri C, and Kikuchi K. Activation of ERK induces phosphorylation of MAPK phosphatase-7, a JNK specific phosphatase, at Ser-446. J Biol Chem. 2003 Aug 22;278(34):32448-56. DOI:10.1074/jbc.M213254200 |
2. Willoughby EA, Perkins GR, Collins MK, and Whitmarsh AJ. The JNK-interacting protein-1 scaffold protein targets MAPK phosphatase-7 to dephosphorylate JNK. J Biol Chem. 2003 Mar 21;278(12):10731-6. DOI:10.1074/jbc.M207324200 |
3. Willoughby EA and Collins MK. Dynamic interaction between the dual specificity phosphatase MKP7 and the JNK3 scaffold protein beta-arrestin 2. J Biol Chem. 2005 Jul 8;280(27):25651-8. DOI:10.1074/jbc.M501926200 |
4. Martell KJ, Seasholtz AF, Kwak SP, Clemens KK, and Dixon JE. hVH-5: a protein tyrosine phosphatase abundant in brain that inactivates mitogen-activated protein kinase. J Neurochem. 1995 Oct;65(4):1823-33. DOI:10.1046/j.1471-4159.1995.65041823.x |
5. Masuda K, Shima H, Watanabe M, and Kikuchi K. MKP-7, a novel mitogen-activated protein kinase phosphatase, functions as a shuttle protein. J Biol Chem. 2001 Oct 19;276(42):39002-11. DOI:10.1074/jbc.M104600200 |
6. Tanoue T, Yamamoto T, Maeda R, and Nishida E. A Novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs. J Biol Chem. 2001 Jul 13;276(28):26629-39. DOI:10.1074/jbc.M101981200 |
7. Kumar GS, Zettl H, Page R, and Peti W. Structural basis for the regulation of the mitogen-activated protein (MAP) kinase p38α by the dual specificity phosphatase 16 MAP kinase binding domain in solution. J Biol Chem. 2013 Sep 27;288(39):28347-56. DOI:10.1074/jbc.M113.499178 |
8. Katagiri C, Masuda K, Urano T, Yamashita K, Araki Y, Kikuchi K, and Shima H. Phosphorylation of Ser-446 determines stability of MKP-7. J Biol Chem. 2005 Apr 15;280(15):14716-22. DOI:10.1074/jbc.M500200200 |
9. Masuda K, Katagiri C, Nomura M, Sato M, Kakumoto K, Akagi T, Kikuchi K, Tanuma N, and Shima H. MKP-7, a JNK phosphatase, blocks ERK-dependent gene activation by anchoring phosphorylated ERK in the cytoplasm. Biochem Biophys Res Commun. 2010 Mar 5;393(2):201-6. DOI:10.1016/j.bbrc.2010.01.097 |
10. Pi X, Wu Y, Ferguson JE 3rd, Portbury AL, and Patterson C. SDF-1alpha stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration. Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5675-80. DOI:10.1073/pnas.0809568106 |