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FLASH GENE
Symbol SHARPIN contributors: mct/shn - updated : 10-06-2013
HGNC name SHANK-associated RH domain interactor
HGNC id 25321
Location 8q24.3      Physical location : 145.153.537 - 145.159.140
Synonym name
  • shank-associated RH domain-interacting protein
  • shank-interacting protein-like 1
  • Synonym symbol(s) PSEC0216, DKFZp434N1923, SIPL1, hSIPL1
    DNA
    TYPE functioning gene
    STRUCTURE 5.60 kb     9 Exon(s)
    MAPPING cloned Y linked N status provisional
    Map cen - D8S1751 - D8S1836 - SHARPIN - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 splicing 1816 - 387 - 2011 21455180
    8 splicing 1691 - - - -
    non-coding RNA
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly Homo sapiensAdultNM_030974
    Digestiveesophagus   highly Homo sapiensAdultNM_030974
     intestinesmall intestinejejunum highly Homo sapiensAdultNM_030974
     intestinesmall intestineileum highly Homo sapiensAdultNM_030974
     intestinesmall intestineduodenum highly Homo sapiensAdultNM_030974
     intestinelarge intestinerectum lowly Homo sapiens
     intestinesmall intestine  moderately Homo sapiensAdultNM_030974
     intestinelarge intestinecolon moderately Homo sapiensAdultNM_030974
     liver   highly Homo sapiensAdultNM_030974
     stomach   highly Homo sapiensAdultNM_030974
    Lymphoid/Immunespleen   moderately Homo sapiensAdultNM_030974
     spleen   moderately Homo sapiensAdultNM_030974
    Nervous    moderately Homo sapiensAdultNM_030974
    Reproductivefemale systemplacenta  moderately Homo sapiensAdultNM_030974
    Respiratorylung   moderately Homo sapiensAdultNM_030974
    Urinarykidney   highly Homo sapiensAdultNM_030974
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal highly Homo sapiensAdultNM_030974
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte Homo sapiensAdultNM_030974
    Skeletonosteoblast Homo sapiens
    Skeletonosteoclast Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a Ub-like (UBL) domain required for the binding to RNF31 to assemble LUBAC
  • a N-terminal 170 AA stretch, which is not well characterized and is absent in RBCK1
  • a Npl4 zinc-finger (NZF) domain
  • shares significant similarity with the N-terminal region of RBCK1 that comprises the UBL and NZF domains and similar to RBCK1 binds ubiquitin via the NZF, whereas its UBL domain is responsible for the interaction with RNF31
  • HOMOLOGY
    interspecies ortholog to Sharpin, Mus musculus
    ortholog to Sharpin, Rattus norvegicus
    ortholog to SHARPIN, Pan troglodytes
    Homologene
    FAMILY
    CATEGORY
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    basic FUNCTION
  • is not an inert scaffold protein, but may play tumor-associated roles during cancer biogenesis
  • may be playing important regulating roles in bone metabolism
  • ubiquitin-binding and ubiquitin-like-domain-containing protein
  • functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC)
  • activates NF-KB and inhibits apoptosis via distinct pathways
  • potentially regulates mitochondria-dependent apoptosis in keratinocytes
  • might play a role in the TLR pathway
  • essential adaptor downstream of the branch point defined by the panr2 mutation in IKBKG
  • controls expression of a subset of TLR2-induced and NFKB– and AP1–dependent genes that overlaps with those affected by the hypomorphic panr2 mutation in IKBKG
  • an important inactivator of beta1-integrins in an RNAi screen
  • inhibits the critical switching of beta1-integrins from inactive to active conformations (
  • has the ability to self-associate into dimers but rather unexpectedly shows that dimerization is not mediated by a coiled coil but that SHARPIN utilizes the pleckstrin homology (PH) superfold as a dimerization module instead
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • Shank family of proteins (also termed CortBP, ProSAP, or Synamon)
  • RBCK1 and EYA1
  • IKBKG
  • activates NFKB1 signaling by forming a linear ubiquitin chain assembly complex with RNF31 (HOIP) and RBCK1 (HOIL1)
  • integrin alpha-subunits
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional        
    causes IHES (idiopathic hypereosinophilic syndrome) with eosinophilic dermatitis by NF-kB activation, and bortezomib may be an effective treatment for skin problems of IHES
    constitutional        
    loss of SHARPIN, similar to loss of Gadkin (AP1AR), is associated with an elevated propensity of cell to migrate, suggesting that signal-dependent control of cell shape and motility is under spatiotemporal control imparted by activators and inhibitors acting at multiple stages of the pathway
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • mutations in the mouse Sharpin gene cause a chronic proliferative dermatitis phenotype, characterized by severe inflammation, eosinophilic dermatitis and defects in secondary lymphoid organ development
  • loss of function of Sharpin leads to activation of NF-KB signaling in skin, resulting in the development of an idiopathic hypereosinophilic syndrome (IHES) with eosinophilic dermatitis in C57BL/KaLawRij-Sharpin(cpdm)/RijSunJ mice
  • siRNA-mediated knockdown of SIPL1 expression inhibited the growth of both HeLa cells and DU145 human prostate carcinoma cells in vitro and in vivo in a xenograft tumor model
  • loss of SHARPIN causes chronic dermatitis and an immunodeficiency in mice
  • Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased beta1-integrin activity