Atypical Phosphatase | Primary Subcellular Localization | MAPK Substrate Specificity | Normal Tissue Expression and Distribution of the mRNA or Protein | Expression in Tumors Relative to Normal Tissue, Consequences of Atypical Expression to Tumor Cell Lines and in Vivo Tumors | Knockout Mice Phenotype | References |
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DUSP3, VHR, T-DSP11 | Nuclear | ERK ∼ JNK ≫ p38 | Constitutive | VHR siRNA-mediated decrease induced cell-cycle arrest in HeLa cells | Kamb et al., 1994; Todd et al., 1999, 2002; Rahmouni et al., 2006; Hoyt et al., 2007; Henkens et al., 2008 | |
STAT5 dephosphorylation | Human: heart, brain, skeletal muscle, breast, ovary | VHR highly expressed in HeLa, SiHa, CaSki, C33, and HT3 cervical cancer cell lines with nuclear localization compared with HT3 primary keratinocytes (from hysterectomies) that have no VHR nuclear staining | ||||
VHR (Y138) may create binding for STAT5 SH2 domain | High-grade squamous intraepithelial lesions and squamous cell carcinomas are associated with strong nuclear and cytoplasmic VHR protein | |||||
VHR (C124→S); VHR (Y138→F); either mutation → dominant negative for STAT5 dephosphorylation | Primary cervical adenocarcinomas and adenocarcinoma in situ are also associated with high VHR staining in cytoplasm but no nuclear immunoreactivity | |||||
VHR (Y138) autodephosphorylation intra- or intermolecular | VHR may be a marker for cervix carcinoma | |||||
DUSP12, GKAP, HYVH-1, LMW-DSP4, T-DSP4, VH1, mVH1 | Cytosolic | No specificity toward MAPK. | Inducible: expression follows cyclin D1 accumulating during G1/S phase in NIH 3T3 | Increased expression owing to increased gene copy number in LS3x, LS21, LS43, and MS8x sarcomas | Munoz-Alonso et al., 2000; Zhang et al., 2000; Aoki et al., 2001; Kresse et al., 2005 | |
May increase level of phospho-ERK1 | Some expression in mouse kidney, liver, lung, heart thymus, spleen, brain, and skeletal muscle | |||||
Dephosphorylates pNPP and a phosphotyrosine -containing peptide “RAYTIDE” but not a phosphoserine-containing peptide | ||||||
Dephosphorylates and accelerates glucokinase activity | ||||||
DUSP13A, MDSP, BEDP | Cytosolic | No specificity toward MAPK | Skeletal muscle (protein) | Chen et al., 2004 | ||
MDSP has phosphatase activity toward P-Tyr and P-Thr | Highest levels in adult mouse | |||||
Unknown substrate | ||||||
DUSP13B, TMDP, TS-DSP6 | No MAPK specificity | Testis: highest levels in adult mouse (protein) | Nakamura et al., 1999; Chen et al., 2004; Kim et al., 2007 | |||
Dephosphorylates P-Tyr (MBP) and P-Thr (MBP) with similar efficiency | ||||||
Possibly active before substrate binding | ||||||
DUSP14, MKP6, MKP-L | At the plasma membrane | JNK > ERK ∼ p38 | Ubiquitous | HCT-116 cell lines transfected with Kruppel-type zinc-finger protein (ZBP-89) up-regulates JNK1/2 phosphorylation by down-regulating MKP-6 (DUSP14) expression, leading to enhanced apoptosis | Marti et al., 2001; Bai et al., 2004 | |
DUSP15, VHY, LMW-DSP10, T-DSP10 | Cytoplasmic face of plasma Membrane (myristolated) | mRNA Testis protein (pachytene spermatocytes) | Alonso et al., 2004b | |||
DUSP18, DUSP20, LMWDSP20 | Cytosolic and nuclear | JNK ≫ p38 ∼ ERK | Adult: ubiquitous | All carcinoma cell lines and cell “normal” lines tested | Wu et al., 2003, 2006b; Jeong et al., 2006 | |
Fetal: all tissues tested | ||||||
Interaction between C-terminal domain of DUSP18 and its catalytic domain may enhance stabilization of catalytic domain and account for its thermal stability; the optimum activity for DUSP18 is at 55°C and 80% of WT activity is retained at 70°C | ||||||
DUSP19, LDP-2, SKRP1, TS-DSP1, DUSP17, LMW-DSP3 | Cytosolic | JNK ≫ ERK ∼ p38 | Mouse: ubiquitous | Nakamura et al., 2002; Zama et al., 2002a, b; Cheng et al., 2003 | ||
SKRP1 also interacts directly with MKK7 and ASK1 | Human adult: heart, lung, liver, pancreas | |||||
DUSP21, LMWDSP21 | Cytosolic and nuclear | Testis | Hood et al., 2002 | |||
DUSP22, LMW-DSP2, TS-DSP-2, VHX, JSP1, JKAP, MKPX | Cytosolic and nuclear (myristolated) | p38 ≫ JNK > ERK | Inducible | LMW-DSP2 interacts directly and dephosphorylates STAT3 in murine testicular GC-1 cells; LMW-DSP2 also prevents STAT3 translocation to the nucleus | JKAP-null mice are borne with predicted mendelian ratios and are healthy throughout adult life | Aoyama et al., 2001; Shen et al., 2001; Alonso et al., 2002; Chen et al., 2002; Sekine et al., 2006, 2007 |
VHX inactivates ERK-2 | Lymphoid cells adult murine tissue: heart, brain, liver, kidney and testis | DUSP22 mRNA increases in response to estrogen in ERα-positive human breast cancer cell lines MCF-7 and T47D | ||||
JKAP associates with MKK7 | Luciferase reporter assay in MCF-7 or HeLa cells: 1) DUSP22 siRNA enhanced estrogen/ERα-induced luciferase activation (HeLa cells were ERα-transfected, MCF-7 endogenous ERα); 2) DUSP22 siRNA reduced dihydrotestosterone/androgen receptor-induced luciferase activation (in androgen receptor HeLa cells); 3) DUSP22 siRNA had no effect on dexamethasone-induced luciferase activation in HeLa cells | |||||
JKAP-null cells have reduced JNK activation in response to cytokines | Pulldown assays indicate that DUSP22 interacts directly with ERα | |||||
JSP1 activates MKK4 | ||||||
LMW-DSP2 dephosphorylates STAT3 | ||||||
DUSP22 dephosphorylates ERα at Ser-118 | ||||||
DUSP23, MOSP, VHZ, LDP-3, DUSP25, FLJ20442 | Cytosolic: apical submembrane area and nuclear: nucleolus | ERK ≫ p38 ∼ JNK | Human fetal tissue: ubiquitous except spleen; human adult: colon, testis, pancreas, liver heart, lung | Alonso et al., 2004a; Takagaki et al., 2004, 2007; Wu et al., 2004a; Agarwal et al., 2008 | ||
Enhances activation of p38 and JNK during osmotic stress via MKK4 and MKK6 activation | Mouse adult: ubiquitously expressed LDP-3 | |||||
DUSP26, MKP8, NATA1, SKRP3, LDP-4 | Nuclear and Golgi apparatus | p38 ≫ JNK ∼ ERK | Mouse: skeletal muscle and brain, cerebellum | Increased copy number of gene in anaplastic thyroid tumors and cell lines; DUSP26 inhibits caspase-3 activity in anaplastic thyroid cell lines | Vasudevan et al., 2005; Hu and Mivechi, 2006; Takagaki et al., 2007; Yu et al., 2007 | |
Mouse LDP-4 expressed in brain except hippocampus | Expression is also increased in retinoblastoma, neuroblastoma, and epithelioblastoma | |||||
DUPD1, DUSP27, FMDSP | Cytosolic | Skeletal muscle, liver and adipose tissue | Friedberg et al., 2007 | |||
DUSP28, VHP | Strausberg et al., 2002 | |||||
PTPMT1, MOSP, PLIP, PNAS-129 | Mitochondrial: anchored to the matrix face of the inner mitochondrial membrane | Currently unknown | Rat: testes, liver, kidney, and endocrine cells of the pancreas | Knockdown of PTPMT1 | Pagliarini et al., 2005 | |
Knockdown of PTPMT1 changes P-Ser/Thr and P-Tyr profiles in mitochondrial proteins | Rat islets and insulinoma cell line INS-1 832/13 express PTPMT1 but not the exocrine-derived cell line PANC-1 | |||||
STYX, hStyxb | Inactive phosphatase owing to Cys→Gly substitution in catalytic site | Ubiquitous | Null males are infertile because of abnormal sperm production. | Wishart et al., 1995; Wishart and Dixon, 2002 | ||
Female offspring of null animals are fertile |
STAT, signal transduction and activator of transcription; pNPP, p-nitrophenyl phosphate; P, phospho; MBP, myelin basic protein; ERα, estrogen receptor-α; VHP, VH1-like phosphatase1