Target Information
Target General Information | Top | |||||
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Target ID |
T12646
(Former ID: TTDI02187)
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Target Name |
Valosin-containing protein p97 (VCP)
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Synonyms |
Valosin-containing protein; Transitional endoplasmic reticulum ATPase; TER ATPase; 15S Mg(2+)-ATPase p97 subunit
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Gene Name |
VCP
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 4 Target-related Diseases | + | ||||
1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
2 | Multiple myeloma [ICD-11: 2A83] | |||||
3 | Myelodysplastic syndrome [ICD-11: 2A37] | |||||
4 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
Function |
Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation. Plays a role in the regulation of stress granules (SGs) clearance process upon arsenite-induced response. Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites. Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage. Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation. Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy. Acts as a negative regulator of type I interferon production by interacting with DDX58/RIG-I: interaction takes place when DDX58/RIG-I is ubiquitinated via 'Lys-63'-linked ubiquitin on its CARD domains, leading to recruit RNF125 and promote ubiquitination and degradation of DDX58/RIG-I. May play a role in the ubiquitin-dependent sorting of membrane proteins to lysosomes where they undergo degradation. May more particularly play a role in caveolins sorting in cells. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway. Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis.
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BioChemical Class |
Acid anhydride hydrolase
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UniProt ID | ||||||
EC Number |
EC 3.6.4.6
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Sequence |
MASGADSKGDDLSTAILKQKNRPNRLIVDEAINEDNSVVSLSQPKMDELQLFRGDTVLLK
GKKRREAVCIVLSDDTCSDEKIRMNRVVRNNLRVRLGDVISIQPCPDVKYGKRIHVLPID DTVEGITGNLFEVYLKPYFLEAYRPIRKGDIFLVRGGMRAVEFKVVETDPSPYCIVAPDT VIHCEGEPIKREDEEESLNEVGYDDIGGCRKQLAQIKEMVELPLRHPALFKAIGVKPPRG ILLYGPPGTGKTLIARAVANETGAFFFLINGPEIMSKLAGESESNLRKAFEEAEKNAPAI IFIDELDAIAPKREKTHGEVERRIVSQLLTLMDGLKQRAHVIVMAATNRPNSIDPALRRF GRFDREVDIGIPDATGRLEILQIHTKNMKLADDVDLEQVANETHGHVGADLAALCSEAAL QAIRKKMDLIDLEDETIDAEVMNSLAVTMDDFRWALSQSNPSALRETVVEVPQVTWEDIG GLEDVKRELQELVQYPVEHPDKFLKFGMTPSKGVLFYGPPGCGKTLLAKAIANECQANFI SIKGPELLTMWFGESEANVREIFDKARQAAPCVLFFDELDSIAKARGGNIGDGGGAADRV INQILTEMDGMSTKKNVFIIGATNRPDIIDPAILRPGRLDQLIYIPLPDEKSRVAILKAN LRKSPVAKDVDLEFLAKMTNGFSGADLTEICQRACKLAIRESIESEIRRERERQTNPSAM EVEEDDPVPEIRRDHFEEAMRFARRSVSDNDIRKYEMFAQTLQQSRGFGSFRFPSGNQGG AGPSQGSGGGTGGSVYTEDNDDDLYG Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T18SEF |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | CB-5083 | Drug Info | Phase 1 | Multiple myeloma | [2], [3], [4] | |
2 | CB-5339 | Drug Info | Phase 1 | Acute myeloid leukaemia | [5] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 2 Inhibitor drugs | + | ||||
1 | CB-5083 | Drug Info | [1] | |||
2 | CB-5339 | Drug Info | [6] |
Chemical Structure based Activity Landscape of Target | Top |
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Co-Targets | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
1 | Protein processing in endoplasmic reticulum | |||||
2 | Legionellosis | |||||
Reactome | [+] 2 Reactome Pathways | + | ||||
1 | Hedgehog ligand biogenesis | |||||
2 | Hh mutants that don't undergo autocatalytic processing are degraded by ERAD |
References | Top | |||||
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REF 1 | Pharmacological targeting of valosin containing protein (VCP) induces DNA damage and selectively kills canine lymphoma cells. BMC Cancer. 2015; 15: 479. | |||||
REF 2 | ClinicalTrials.gov (NCT02243917) A Phase 1 Study Evaluating CB-5083 in Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 5 | ClinicalTrials.gov (NCT04402541) Study of CB-5339 in Acute Myeloid Leukemia or Myelodysplastic Syndrome. U.S. National Institutes of Health. | |||||
REF 6 | Clinical pipeline report, company report or official report of Cleave Therapeutics. |
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