Disease relevance of DUSP3

• We report here that VHR, a Vaccinia virus VH1-related dual-specific protein phosphatase that inactivates the mitogen-activated kinases Erk2 and Jnk, is phosphorylated at Y138 by ZAP-70 [1].
• This has resulted in the isolation and precise localisation of eight novel genes, including a novel G protein and an endogenous retrovirus related to the HERV-K family, and the previously described dual-specificity VHR phosphatase and MOX1 homeobox genes [2].
• In the present study, we have investigated the origin of the low pKa by analyzing the electrostatic properties of four different protein-tyrosine phosphatases: Yersinia PTP (bacteria), PTP1B (human), VHR (human), and low molecular weight phosphatase (bovine) [3].
• STATE OF ART: During the last decade, different definitions of VHR factors in childhood ALL have been a crucial issue, so that therapeutic results of single or multicenter studies were difficult to compare [4].
• Men with severe vertebral deformity (VHR < mean - 4 SD below mean) had much lower body weight, fat mass, and bone mineral density (BMD) than controls [5].

High impact information on DUSP3

• Here, the crystal structure of a human DSP, vaccinia H1-related phosphatase (or VHR), was determined at 2.1 angstrom resolution [6].
• A shallow active site pocket in VHR allows for the hydrolysis of phosphorylated serine, threonine, or tyrosine protein residues, whereas the deeper active site of protein tyrosine phosphatases (PTPs) restricts substrate specificity to only phosphotyrosine [6].
• A "recognition region," connecting helix alpha1 to strand beta1, may determine differences in substrate specificity between VHR, the PTPs, and other DSPs [6].
• Tyr138 phosphorylation was required for VHR to inhibit the Erk2-Elk-1 pathway and, conversely, the VHR(Y138F) mutant augmented TCR-induced Erk2 kinase and activation of the gene encoding interleukin 2 [1].
• Tyrosine phosphorylation of VHR phosphatase by ZAP-70 [1].

Chemical compound and disease context of DUSP3

• The recombinant human Vaccinia virus H1-related protein tyrosine phosphatase, (VHR PTPase) possesses intrinsic Tyr and Thr/Ser phosphatase activities [7].
• In this work, we investigated the structural role of histidine array in HC(X)(5)RS motif of the vaccinia H1-related protein phosphatase (VHR), using site-directed mutagenesis in conjunction with an extensive kinetic analysis [8].
• By use of recombinant enzymes, the effects of H2O2 on three PTPs [PTP1, LAR (leukocyte antigen-related), and VHR (vaccinia H1-related)] and three distinct serine/threonine protein phosphatases (PPs: PP2Calpha, calcineurin, and lambda phosphatase) were determined [9].

Biological context of DUSP3

• Secondary structure prediction and molecular modeling of rVH6 based on the x-ray structure of the dual specificity protein tyrosine phosphatase, VHR, further supported the assignment of residues 134-381 to the core catalytic domain of rVH6 [10].
• We speculate that VHR may represent a dual specificity phosphatase responsible for activation of cdk-cyclin complex(es) at a still undetermined stage of the cell cycle [11].
• VHR injection done in conjunction with progesterone or insulin treatment resulted in highly synergized GVBD responses showing much faster kinetics than that produced by VHR or either hormone alone [11].
• Transfection studies in COS-1 cells demonstrated that in vivo phosphorylation of epidermal growth factor-stimulated ERK depended on VHR protein levels [12].
• Based on the structure-activity relationships for VHR inhibition by RK-682 derivatives, we constructed a binding model using molecular dynamics calculation [13].

Anatomical context of DUSP3

• The biological actions of VHR in oocytes clearly distinguish it from other dual specificity phosphatases, which have shown inhibitory effects when tested in oocytes [11].
• For HR/VHR patients, inability to salvage after relapse (nearly all of which were in the bone marrow) remains a significant clinical problem [14].
• T-cell ALL (T-ALL) patients with poor in vivo response to initial treatment represented the largest homogeneous subgroup within VHR patients [15].

Associations of DUSP3 with chemical compounds

• A mutant VHR protein missing an essential cysteine residue for its in vitro phosphatase activity completely lacked activity in injected oocytes [11].
• The reaction of DHTGFLpTEpYVATR with VHR is ordered, with rapid dephosphorylation on tyrosine occurring first followed by slow dephosphorylation on threonine [16].
• When VHR was incubated with a 32P-labeled phosphotyrosine-containing substrate and then rapidly denatured, enzyme-associated 32P was evident following SDS-polyacrylamide gel electrophoresis [7].
• VHR-associated 32P was sensitive to iodine but insensitive to pyridine and hydroxylamine [7].
• Furthermore, VHR phosphatase could be selectively inactivated by the alkylating agent iodoacetate [7].
• The tyrosine kinase Tyk2, which mediates the phosphorylation of STAT5, was also responsible for the phosphorylation of VHR at Tyr(138) [17].

Other interactions of DUSP3

• Interestingly, NU-154 inhibited human PTP1B in vitro with an IC(50) value of 24 +/- 1 microM and showed little inhibition against Cdc25B, MKP-1, and VHR phosphatases [18].
• Less relatedness was observed with VHR and VH1 dual specificity phosphatases of human and vaccinia virus, respectively [19].

Analytical, diagnostic and therapeutic context of DUSP3

• CNS leukemia relapse (isolated or combined with bone marrow) occurred in four of 82 SR patients who received 18 Gy of cranial irradiation and four of 138 HR and VHR patients who received 24 Gy [20].
• RESULTS: At a median follow-up of 9.2 years, the 9-year event-free survival (EFS +/- SE) was 75% +/- 2% for all 369 patients, 77% +/- 4% for the 142 SR patients, and 73% +/- 3% for the 227 HR/VHR patients (P =.37 comparing SR and HR/VHR) [14].
• Tyr-78 of VHR turns out to be the invariant Tyr reported in several protein-tyrosine phosphatases by a structure-based sequence alignment [8].
• An expression and purification method was developed to obtain the recombinant human dual-specific protein tyrosine phosphatase (PTPase) VHR in quantities suitable for both kinetic studies and crystallization [16].
• Among children with high-risk (HR) ALL there are subgroups with very-high-risk (VHR) features and poor prognosis despite developments in conventional chemotherapy for childhood ALL [21].

References