Alternative titles; symbols
HGNC Approved Gene Symbol: DUSP4
Cytogenetic location: 8p12 Genomic coordinates (GRCh38): 8:29,333,064-29,350,684 (from NCBI)
Dual-specificity phosphatases (DUSPs) constitute a large heterogeneous subgroup of the type I cysteine-based protein-tyrosine phosphatase superfamily. DUSPs are characterized by their ability to dephosphorylate both tyrosine and serine/threonine residues. DUSP4 belongs to a class of DUSPs, designated MKPs, that dephosphorylate MAPK (mitogen-activated protein kinase) proteins ERK (see 601795), JNK (see 601158), and p38 (see 600289) with specificity distinct from that of individual MKP proteins. MKPs contain a highly conserved C-terminal catalytic domain and an N-terminal Cdc25 (see 116947)-like (CH2) domain. MAPK activation cascades mediate various physiologic processes, including cellular proliferation, apoptosis, differentiation, and stress responses (summary by Patterson et al., 2009).
By screening a placenta library with a DUSP1 (600714) cDNA, Guan and Butch (1995) identified cDNAs encoding DUSP4, which they called HVH2 based on its similarity to the cellular proteins homologous to the VH1 phosphatase encoded by the vaccinia virus. Northern blot analysis revealed that DUSP4 is expressed as 2.5- and 6-kb mRNAs in placenta and, at lower levels, in pancreas. The sequence of the predicted 394-amino acid DUSP4 protein was 62% and 55% identical to those of DUSP1 and PAC1 (DUSP2; 603068), respectively. Like DUSP1 and DUSP6 (602748), the N-terminal region of DUSP4 shares significant identity with CDC25 (157680). By immunofluorescence of mammalian cells expressing epitope-tagged protein, Guan and Butch (1995) found that DUSP4 was localized within the nucleus.
Guan and Butch (1995) found that purified recombinant DUSP4 specifically hydrolyzed the phosphothreonine and phosphotyrosine residues of the activated MAP kinases ERK1 (601795) and ERK2 (176948). Expression of DUSP4 in mammalian cells blocked activation of a MAP kinase-regulated reporter gene. These results led Guan and Butch (1995) to suggest that DUSP4 plays a role in the MAP kinase signal transduction pathway.
Transgenic mice homozygous for a his222-to-pro (H222P) mutation in the Lmna gene (150330) are a model for cardiomyopathy due to LMNA mutations (see 181350). Choi et al. (2012) found that ERK activation in H222P/H222P mice specifically upregulated expression of DUSP4 in cardiac muscle, with much lower Dusp4 induction in quadriceps muscle, and no Dusp4 induction in tongue, kidney, and liver. Dusp4 overexpression in cultured C2C12 muscle cells or targeted to mouse heart resulted in activation of the Akt (see AKT1; 164730)-Mtor (FRAP1; 601231) metabolic signaling pathway, leading to impaired autophagy and abnormal cardiac metabolism, similar to findings in H222P/H222P mice. Conversely, knockdown of Dusp4 in C2C12 cells decreased Akt activation and enhanced autophagy.
By fluorescence in situ hybridization, Smith et al. (1997) mapped the DUSP4 gene to 8p12-p11.
Choi, J. C., Wu, W., Muchir, A., Iwata, S., Homma, S., Worman, H. J. Dual specificity phosphatase 4 mediates cardiomyopathy caused by lamin A/C (LMNA) gene mutation. J. Biol. Chem. 287: 40513-40524, 2012. [PubMed: 23048029] [Full Text: https://doi.org/10.1074/jbc.M112.404541]
Guan, K.-L., Butch, E. Isolation and characterization of a novel dual specific phosphatase, HVH2, which selectively dephosphorylates the mitogen-activated protein kinase. J. Biol. Chem. 270: 7197-7203, 1995. [PubMed: 7535768] [Full Text: https://doi.org/10.1074/jbc.270.13.7197]
Patterson, K. I., Brummer, T., O'Brien, P. M., Daly, R. J. Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem. J. 418: 475-489, 2009. [PubMed: 19228121] [Full Text: https://doi.org/10.1042/bj20082234]
Smith, A., Price, C., Cullen, M., Muda, M., King, A., Ozanne, B., Arkinstall, S., Ashworth, A. Chromosomal localization of three human dual specificity phosphatase genes (DUSP4, DUSP6, and DUSP7). Genomics 42: 524-527, 1997. [PubMed: 9205128] [Full Text: https://doi.org/10.1006/geno.1997.4756]