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FLASH GENE
Symbol USP6 contributors: mct/pgu - updated : 09-02-2015
HGNC name ubiquitin specific protease 6 (Tre-2 oncogene)
HGNC id 12629
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • at its N terminus a TBC domain,(Tre-2/Bub2/Cdc16) domain predicted to encode GTPase-activating proteins (GAPs) for Rab family G proteins that mediates binding to the ARF6 GTPase
  • a ubiquitin-specific protease at its C terminus
    • HOMOLOGY
    Homologene
    FAMILY
  • peptidase C19 family
  • TBC family
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    basic FUNCTION
  • regulator of the ARF6-regulated plasma membrane recycling system through TBC domains
  • ubiquitin specific protease, clearing bonds between UB and an unfolded polypeptide or UB and small substituents
  • ubiquitin-specific protease (USP), with a TBC domain that mediates binding to the Arf6 GTPase
  • sufficient to induce expression of MMP9 and MMP10, in a manner requiring its USP activity, but not its ability to bind Arf6
  • sufficient to initiate tumorigenesis, and MMPs are novel TRE17 effectors that likely contribute to ABC (aneurysmal bone cyst) pathogenesis
  • role in dysregulation of autocrine bone morphogenetic protein (BMP) signaling is an important mechanism by which USP6 arrests osteoblastic maturation
  • appears to simultaneously inhibit osteoblast maturation and stimulate osteoclast activity
  • critical role for NFKB1 in USP6-mediated tumorigenesis, suggesting that NFKB1 inhibitors may function as effective therapeutic agents in the treatment of aneurysmal bone cyst (ABC)
  • implicated as a key etiological factor in aneurysmal bone cyst (ABC), a locally recurrent pediatric bone tumor,
  • regulator of both cell migration and division
  • ubiquitylation of clathrin-independent endocytosis (CIE) cargo proteins by MARCH8 was reversed by USP6, suggesting that USP6 leads to deubiquitylation of CIE cargo proteins
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • targets the Arf family GTPase ARF6, which regulates plasma membrane-endosome trafficking
  • ubiquitous calcium (Ca2+)-binding protein calmodulin (CALM) is a novel binding partner (CALM1 bound directly to USP in a Ca2+-dependent manner, and regulates ubiquitination)
  • induces transcription of MMP9 through activation of nuclear factor-KB (NF-KB), mediated in part by the GTPase RhoA and its effector kinase, ROCK
  • first de-ubiquitinating enzyme to activate NFKB1
  • oncogenic potential of USP6 is linked to its ability to integrate cell migration and cytokinesis by regulating ARF6/ACAP1
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   translocation    
    translocated at high frequency in aneurysmal bone cyst (ABC), a pediatric osseous neoplasm
    tumoral fusion      
    t(16;17)(q22;p13) the most frequent chromosomal aberration with translocation generating a CDH11-USP6 fusion gene in aneurysmal bone cyst
    tumoral   translocation    
    t(17;17) resulting in a COL1A1-USP6 chimeric gene in aneurysmal bone cyst
    tumoral     --over  
    attenuated osteoblast maturation caused by USP6 overexpression may contribute to the bone loss/destruction observed in aneurysmal bone cyst
    tumoral fusion      
    rearrangements of both USP6 and SS18, but histologic features were consistent with aneurysmal bone cyst throughout the lesion
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS