Molecule Information

General Information of the Molecule (ID: Mol04372)

• Name: Ubiquitin carboxyl-terminal hydrolase 5 (USP5) ,Homo sapiens
• Synonyms: Deubiquitinating enzyme 5; Isopeptidase T; Ubiquitin thioesterase 5; Ubiquitin-specific-processing protease 5
• Molecule Type: Protein
• Gene Name: USP5
• Gene ID: 8078
• Sequence:
  MAELSEEALLSVLPTIRVPKAGDRVHKDECAFSFDTPESEGGLYICMNTFLGFGKQYVER
  HFNKTGQRVYLHLRRTRRPKEEDPATGTGDPPRKKPTRLAIGVEGGFDLSEEKFELDED
  V KIVILPDYLEIARDGLGGLPDIVRDRVTSAVEALLSADSASRKQEVQAWDGEVRQVSK
  HA FSLKQLDNPARIPPCGWKCSKCDMRENLWLNLTDGSILCGRRYFDGSGGNNHAVEHY
  RET GYPLAVKLGTITPDGADVYSYDEDDMVLDPSLAEHLSHFGIDMLKMQKTDKTMTEL
  EIDM NQRIGEWELIQESGVPLKPLFGPGYTGIRNLGNSCYLNSVVQVLFSIPDFQRKYV
  DKLEK IFQNAPTDPTQDFSTQVAKLGHGLLSGEYSKPVPESGDGERVPEQKEVQDGIAP
  RMFKAL IGKGHPEFSTNRQQDAQEFFLHLINMVERNCRSSENPNEVFRFLVEEKIKCLA
  TEKVKYT QRVDYIMQLPVPMDAALNKEELLEYEEKKRQAEEEKMALPELVRAQVPFSSC
  LEAYGAPE QVDDFWSTALQAKSVAVKTTRFASFPDYLVIQIKKFTFGLDWVPKKLDVSI
  EMPEELDIS QLRGTGLQPGEEELPDIAPPLVTPDEPKGSLGFYGNEDEDSFCSPHFSSP
  TSPMLDESVI IQLVEMGFPMDACRKAVYYTGNSGAEAAMNWVMSHMDDPDFANPLILPG
  SSGPGSTSAAA DPPPEDCVTTIVSMGFSRDQALKALRATNNSLERAVDWIFSHIDDLDA
  EAAMDISEGRSA ADSISESVPVGPKVRDGPGKYQLFAFISHMGTSTMCGHYVCHIKKEG
  RWVIYNDQKVCAS EKPPKDLGYIYFYQRVAS
• Function: Deubiquitinating enzyme that participates in a wide range ofcellular processes by specifically cleaving isopeptide bonds betweenubiquitin and substrate proteins or ubiquitin itself. Affects therebyimportant cellular signaling pathways such as NF-kappa-B, Wnt/beta-catenin, and cytokine production by regulating ubiquitin-dependentprotein degradation. Participates in the activation of the Wntsignaling pathway by promoting FOXM1 deubiquitination and stabilizationthat induces the recruitment of beta-catenin to Wnt target genepromoter . Regulates the assembly and disassembly ofheat-induced stress granules by mediating the hydrolysis of unanchoredubiquitin chains . Promotes lipopolysaccharide-inducedapoptosis and inflammatory response by stabilizing the TXNIP protein. Affects T-cell biology by stabilizing the inhibitoryreceptor on T-cells PDC1 . Acts as a negativeregulator of autophagy by regulating ULK1 at both protein and mRNAlevels . Acts also as a negative regulator of type Iinterferon production by simultaneously removing both 'Lys-48'-linkedunanchored and 'Lys-63'-linked anchored polyubiquitin chains on thetranscription factor IRF3 . Modulates the stability ofDNA mismatch repair protein MLH1 and counteracts the effect of theubiquitin ligase UBR4 . Upon activation by insulin, itgets phosphorylated through mTORC1-mediated phosphorylation to enhanceYTHDF1 stability by removing 'Lys-11'-linked polyubiquitination. May also deubiquitinate other substrates such as thecalcium channel CACNA1H . {ECO:0000250|UniProtKB:P56399,ECO:0000269|PubMed:19098288, ECO:0000269|PubMed:26912724,ECO:0000269|PubMed:29567855, ECO:0000269|PubMed:37208329,ECO:0000269|PubMed:37534934, ECO:0000269|PubMed:39032648,ECO:0000269|PubMed:39761299, ECO:0000269|PubMed:39900921}.
• Uniprot ID: UBP5_HUMAN
• Ensembl ID: ENSG0000011166714
• HGNC ID: HGNC:12628

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Ripretinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastrointestinal stromal tumor [ICD-11: 2B5B.0] [1]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Resistant Drug: Ripretinib
• Molecule Alteration: Expression; Up-regulation
• Cell Pathway Regulation: TRIM21-USP5-MDH2 signaling pathway; Regulation; N.A.
• Experiment for Molecule Alteration: Proteome-ubiquitinome sequencing assay
• Experiment for Drug Resistance: MS analysis
• Mechanism Description: Increased levels of the USP5 protein and decreased ubiquitination in ripretinib-resistant GISTs are detected.TRIM21 governs USP5 expression via ubiquitination, and USP5 regulates MDH2 expression through deubiquitination, consequently fostering ripretinib resistance in GIST.

References

• Ref 1: USP5 Promotes Ripretinib Resistance in Gastrointestinal Stromal Tumors by MDH2 Deubiquition. Adv Sci (Weinh). 2024 Sep;11(34):e2401171.