Disease relevance of RNF19

• Our results indicate that VCPs functionally regulate Dorfin through direct interaction and that their functional interplay may be related to the process of UBI formation in neurodegenerative disorders, such as ALS or PD [1].
• Here, we report that affinity-purified anti-Dorfin antibody labeled ubiquitylated inclusions of Parkinson's disease, dementia with Lewy bodies disease, multiple system atrophy, and sporadic and familial ALS [2].
• Dorfin, a RING-IBR type ubiquitin ligase (E3), can ubiquitylate mutant superoxide dismutase 1, the causative gene of familial amyotrophic lateral sclerosis (ALS) [1].
• Mutational dysfunction of PARKIN gene, which encodes a double RING finger protein and has ubiquitin ligase E3 activity, is the major cause of autosomal recessive juvenile Parkinsonism. Although many studies explored the functions of Parkin, its biochemical character is poorly understood [3].
• The scaffold p38 protein was expressed in Escherichia coli and purified to homogeneity as a His-tagged protein [4].

High impact information on RNF19

• The involvement of p38 mitogen-activated protein kinase (MAPK) was further confirmed by a resveratrol-mediated phosphorylation of p38 protein in both cell lines [5].
• Exposure of PC-3 cells to 10 microM PEITC also resulted in a time-dependent activation of p38 protein kinase that was associated with increased phosphorylation of activating transcription factor 2 at Thr71 [6].
• Even though the PEITC-induced activation of p38 protein kinase was abrogated in the presence of its specific inhibitor SB202190, inhibition of p38 protein kinase activation did not prevent PEITC-induced apoptosis [6].
• We report in this study that NKLAM contains a cysteine-rich really interesting new gene (RING) in between RING-RING domain, and that this domain possesses strong homology to the RING domain of the known E3 ubiquitin ligase, Dorfin [7].
• Because endogenous CaR in Madin-Darby canine kidney cells is also subject to degradation from the endoplasmic reticulum, dorfin-mediated ubiquitination may contribute to a general mechanism for CaR quality control during biosynthesis [8].

Chemical compound and disease context of RNF19

• RESULTS: (1) Both cisplatin and DTT induced apoptosis in the esophageal cancer cell line Eca109 as shown by DNA ladder formation; (2) As detected by antibodies specific for the phosphorylated P38 protein (p-P38), both cisplatin and DTT treatments activated the stress-activated enzyme, MAP kinase P38 [9].

Biological context of RNF19

• Dorfin prevents cell death by reducing mitochondrial localizing mutant superoxide dismutase 1 in a neuronal cell model of familial amyotrophic lateral sclerosis [10].
• The p38 protein is a moderately hydrophobic protein, displays a putative leucine-zipper motif, and shares a sequence pattern with protein domains that are involved in protein-protein interactions [11].
• Using the human lung alveolar epithelial cancer cell line A549, we investigated the role of reactive oxygen species (ROS), extracellular signal-regulated protein kinase (ERK), and p38 protein kinase in vanadate-induced cell growth arrest [12].
• JNK and p38 protein kinases are involved in the signal transduction of apoptotic stimulus [13].
• Dorfin has sequence homology with parkin, which is interesting because mutations in the parkin gene associate with early-onset Parkinson's disease [14].

Anatomical context of RNF19

• The Dorfin mRNA transcript was 4.4 kb and expressed ubiquitously in many organs as well as in the central nervous system, including the spinal cord [15].
• Dorfin is localized in the centrosome and probably functions in the microtubule organizing centers [15].
• Treatment with MG132, a potent proteasome inhibitor, resulted in the accumulation of ubiquitinated Dorfin and Dorfin-associated cellular proteins in cultured cells [15].
• In this paper we report that Dorfin, a RING finger-type E3 ubiquitin ligase, is predominantly localized in the inclusion bodies of familial ALS with a copper/zinc superoxide dismutase (SOD1) mutation as well as sporadic ALS [16].
• These results suggest that reducing the accumulation of mutant SOD1 in the mitochondria may be a new therapeutic strategy for mutant SOD1-associated FALS, and that Dorfin may play a significant role in this [10].

Associations of RNF19 with chemical compounds

• VCP(K524A), a dominant negative form of VCP, reduced the E3 activity of Dorfin against mutant superoxide dismutase 1, whereas it had no effect on the autoubiquitylation of Parkin [1].
• Glycerol gradient centrifugation analysis showed that endogenous Dorfin consisted of a 400-600-kDa complex and was co-immunoprecipitated with endogenous VCP [1].
• Aloe-emodin (40 microM)-induced apoptosis of H460 cells involves modulation of cAMP-dependent protein kinase, protein kinase C, Bcl-2, caspase-3 and p38 protein expression [17].
• The anticancer agent methyl jasmonate induces activation of stress-regulated c-Jun N-terminal kinase and p38 protein kinase in human lymphoid cells [18].
• HIV-gp120 enhancement of IL-1beta-induced NO(2)(-) production was blocked by 10 microM of SB-203580 (SB), a selective p38 protein kinase inhibitor (3.6 +/- 0.2 vs. 6.6 +/- 0.6 micromol/1. 25 x 10(5) cells/48 h, IL-1beta + gp120 + SB vs. IL-1beta + gp120, respectively; n = 12, P </= 0.5) [19].

Physical interactions of RNF19

• In vitro experiments showed that Dorfin interacted directly with VCP through its C-terminal region [1].

Enzymatic interactions of RNF19

• We have previously reported that in thrombin-stimulated human platelets, cytosolic phospholipase A(2) (cPLA2) is phosphorylated on Ser-505 by p38 protein kinase and on Ser-727 by an unknown kinase [20].

Other interactions of RNF19

• Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1 [21].
• High through-put analysis using mass spectrometry identified VCP as a candidate of Dorfin-associated protein [1].
• However, because we failed to show the direct binding of alpha-synuclein with Dorfin, future investigations into the binding partner(s) of Dorfin will be needed to deepen our understanding of the pathophysiology of alpha-synucleinopathy and ALS [2].
• There was no activation of JNK or p38 protein kinases [22].
• Exercise increased total and nuclear p38 phosphorylation and association with MEF-2, without changes in total or nuclear p38 protein abundance [23].

Analytical, diagnostic and therapeutic context of RNF19

• To improve its stability and enhance its E3 activity, we developed chimeric proteins containing the substrate-binding hydrophobic portion of Dorfin and the U-box domain of the carboxyl terminus of Hsc70-interacting protein (CHIP), which has strong E3 activity through the U-box domain [24].
• By immunohistochemistry, the expression of all p38 MAPK isoforms was localized to the synovial lining layer as well as to blood vessels [25].
• This phosphorylation pattern was confirmed in immunoprecipitation studies in which activated p38 MAPK from synovial tissue extracts was identified as p38 MAPKalpha and -gamma but not p38 MAPKbeta or -delta [25].
• The expression and activation of the alpha, beta, gamma, and delta isoforms of p38 MAPK were examined by immunoblotting, immunoprecipitation, and immunohistochemistry [25].
• Employing Western blot analysis and immunohistochemical studies, we found that GTP resulted in inhibition of UVB-induced: (i) phosphorylation of extracellular-signal-regulated kinases (ERK1/2), (ii) c-Jun N-terminal kinases, and (iii) p38 protein expression [26].

References