Alternative titles; symbols
HGNC Approved Gene Symbol: DUSP3
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38): 17:43,766,125-43,778,977 (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. They have been implicated as major modulators of critical signaling pathways. DUSP3 contains the consensus DUSP C-terminal catalytic domain but lacks the N-terminal CH2 domain found in the MKP (mitogen-activated protein kinase phosphatase) class of DUSPs (see 600714). DUSP3 was originally designated VHR because of its close similarity to VH1, a key gene in vaccinia virus (summary by Patterson et al., 2009).
VH1-related phosphatase in vitro dephosphorylates a variety of substrates at both serine and tyrosine residues (Ishibashi et al., 1992). In a search for expressed sequences in the region of 17q21 occupied by the gene for early-onset breast cancer (BRCA1; 113705), Kamb et al. (1994) isolated a gene located approximately 100 kb proximal to D17S78 that was identical to a cDNA sequence for VHR in GenBank. They found by a zoo blot that the VHR gene is conserved through evolution. Northern blot analysis indicated that the gene is expressed in both breast and ovarian tissue. However, a mutation screen in both breast cancer pedigrees and in sporadic tumors was negative, leading to the conclusion that VHR is probably not BRCA1.
Jones et al. (1994) found the dual-specificity VHR phosphatase in the course of producing a detailed physical and transcriptional map of the 400-kb region within the narrowest flanking markers known to contain the BRCA1 gene.
Alonso et al. (2003) noted that VHR suppresses T-cell receptor (TCR)-induced activation of ERK2 (176948) and JNK (601158). They extended this finding by showing that VHR expression reduced activation of an NFAT1 (600489)-AP1 (165160)-driven reporter and TCR signaling to interleukin-2 (IL2; 147680). Confocal microscopy demonstrated that phosphorylated VHR accumulated at the immune synapse between the T cell and the antigen-presenting cell in the presence of antigen. VHR phosphorylation occurred at tyr138, and both phosphorylation and function required ZAP70 (176947). Mutation analysis showed that tyr138 is the major residue phosphorylated by ZAP70, followed by tyr38. Alonso et al. (2003) proposed that tyrosine phosphorylation of VHR affects protein-protein interaction, subcellular location, or substrate targeting, given that tyr138 is located on the opposite side of the VHR catalytic center.
Using knockdown and overexpression analysis, Kang and Kim (2006) showed that Vrk3 (619771) suppressed ERK phosphorylation in mouse HT22 cells. Downregulation of ERK activity by Vrk3 took place in the nucleus, where the phosphatase Vhr interacted and colocalized with Vrk3 and was required for ERK downregulation. Further analysis demonstrated that Vrk3 bound directly to Vhr to enhance Vhr phosphatase activity, and Vhr specifically dephosphorylated and inactivated ERKs in the nucleus.
Song et al. (2016) found that treatment of SH-SY5Y cells with glutamate induced translocation of HSP70 (see 140550) and VHR from cytoplasm to nucleus, where they interacted to enhance VHR phosphatase activity. Nuclear translocation of HSP70 by glutamate was necessary for its interaction with VHR and was facilitated by VRK3, as VRK3 also interacted with HSP70. Glutamate treatment induced ERK activity in SH-SY5Y cells, which in turn transcriptionally upregulated expression of HSP70 and VRK3 to enhance phosphatase activity of VHR in the nucleus to prevent cell death that could be caused by excitotoxicity resulted from persistent ERK activity. The same protective effect against glutamate excitotoxicity-induced cell death was confirmed in mouse cortical neurons by in vitro analysis and by in vivo analysis with Vrk3-deficient mice. Furthermore, analysis with brain lysates from human patients showed that increased expression and nuclear localization of HSP70 suppressed beta-amyloid protein (104760) accumulation and neuronal cell death in brains of AD and PD patients.
Kamb et al. (1994) identified the DUSP3 gene on chromosome 17q21.
Alonso, A., Rahmouni, S., Williams, S., van Stipdonk, M., Jaroszewski, L., Godzik, A., Abraham, R. T., Schoenberger, S. P., Mustelin, T. Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nature Immun. 4: 44-48, 2003. [PubMed: 12447358] [Full Text: https://doi.org/10.1038/ni856]
Ishibashi, T., Bottaro, D. P., Chan, A., Miki, T., Aaronson, S. A. Expression cloning of a human dual-specificity phosphatase. Proc. Nat. Acad. Sci. 89: 12170-12174, 1992. [PubMed: 1281549] [Full Text: https://doi.org/10.1073/pnas.89.24.12170]
Jones, K. A., Black, D. M., Brown, M. A., Griffiths, B. L., Nicolai, H. M., Chambers, J. A., Bonjardim, M., Xu, C.-F., Boyd, M., McFarlane, R., Korn, B., Poustka, A., North, M. A., Schalkwyk, L., Lehrach, H., Solomon, E. The detailed characterisation of a 400 kb cosmid walk in the BRCA1 region: identification and localisation of 10 genes including a dual-specificity phosphatase. Hum. Molec. Genet. 3: 1927-1934, 1994. [PubMed: 7874108]
Kamb, A., Futreal, P. A., Rosenthal, J., Cochran, C., Harshman, K. D., Liu, Q., Phelps, R. S., Tavtigian, S. V., Tran, T., Hussey, C., Bell, R., Miki, Y., Swensen, J., Hobbs, M. R., Marks, J., Bennett, L. M., Barrett, J. C., Wiseman, R. W., Shattuck-Eidens, D. Localization of the VHR phosphatase gene and its analysis as a candidate for BRCA1. Genomics 23: 163-167, 1994. [PubMed: 7829067] [Full Text: https://doi.org/10.1006/geno.1994.1473]
Kang, T.-H., Kim, K.-T. Negative regulation of ERK activity by VRK3-mediated activation of VHR phosphatase. Nature Cell Biol. 8: 863-869, 2006. [PubMed: 16845380] [Full Text: https://doi.org/10.1038/ncb1447]
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]
Song, H., Kim, W., Kim, S.-H., Kim, K.-T. VRK3-mediated nuclear localization of HSP70 prevents glutamate excitotoxicity-induced apoptosis and A-beta accumulation via enhancement of ERK phosphatase VHR activity. Sci. Rep. 6: 38452, 2016. [PubMed: 27941812] [Full Text: https://doi.org/10.1038/srep38452]