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FLASH GENE
Symbol XIAP contributors: shn/mct - updated : 19-10-2017
HGNC name X-linked inhibitor of apoptosis
HGNC id 592
Corresponding disease
XLP2 lymphoproliferative syndrome, 2
Location Xq25      Physical location : 122.994.047 - 123.047.821
Synonym name
  • baculoviral IAP repeat-containing 4
  • apoptosis inhibitor 3
  • IAP-like protein
  • X-linked inhibitor of apoptosis protein
  • E3 ubiquitin-protein ligase XIAP
  • mammalian IAP Homolog A
  • Synonym symbol(s) API3, ILP1, MIHA, BIRC4, HILP, XLP2, FLJ26913, IAP-3, hIAP-3
    EC.number 2.3.2.27
    DNA
    TYPE functioning gene
    STRUCTURE 54.17 kb     7 Exon(s)
    text structure an internal ribosome entry site (IRES) in the 5'UTR
    MAPPING cloned Y linked N status confirmed
    Map cen - DXS9909 - DXS8098 - XIAP - DXS8057 - DXS8093 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    7 - 8413 57 497 - 2017 28040451
    7 - 8427 - 497 - 2017 28040451
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveesophagus   highly
     intestinelarge intestinecolon  
    Endocrinepancreas   highly
    Lymphoid/Immunelymph node   highly
     spleen    
    Reproductivemale systemprostate   
    Urinarykidney   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte
    Blood/Hematopoieticneutrophil
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • three baculovirus IAP repeat (BIR1-2 domains required for inhibition of caspase 3/7)
  • the BIR1 domain directly interacts with MA1P3K7IP1 to induce NF-kappaB activation
  • a C-terminal RING zinc finger domain (BIR3 Ring inhibitor of caspase 9), mediating MAP3K7 polyubiquitination, which then targets this molecule for proteosomal degradation, and is essential for NOD2 signaling
  • BIR and RING finger domains of XIAP contain multiple cysteine residues and are potential targets for S-nitrosylation
  • conjugated ubiquitinated
    mono polymer homomer , monomer , dimer
    HOMOLOGY
    interspecies ortholog to Xiap, Mus musculus
    ortholog to Xiap, Rattus norvegicus
    ortholog to xiap, Danio rerio
    ortholog to XIAP, Pan troglodytes
    intraspecies homolog to NAIP
    Homologene
    FAMILY
  • IAP family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    text
  • VGLL4 triggers a relocalization of XIAP from the cytoplasm to the nucleus
  • basic FUNCTION
  • a direct inhibitor of cell-death proteases
  • inhibitor of apoptosis through binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2
  • antiapoptosis activity in a variety of apoptosis inducing conditions
  • has a ubiquitin protein ligase activity in response to apoptotic stimuli
  • involved in the protection of the neonatal brain against hypoxia-ischemia
  • potent suppressor of apoptosis that directly inhibits specific members of the caspase family (caspase 3, 7, 9) of cysteine proteases, playing a role in the control of intracellular copper levels
  • playing an essential role in the cell death mechanism of injured motoneurons in collaboration with BIRC4BP, BIRC3, BIRC2
  • required for the survival and/or differentiation of NKT cells, and potent regulator of lymphocyte homeostasis
  • functioning as ubiquitin ligase toward mature CASP9 and DIABLO to inhibit apoptosis
  • inhibits c-Jun N-terminal kinase 1 (MAPK8) activation by transforming growth factor beta1 (TGF-beta1) through ubiquitin-mediated proteosomal degradation of the TGF-beta1-activated kinase 1 (MAP3K7)
  • can function as a cofactor in the regulation of gene expression by transforming growth factor-beta (TGF-beta)
  • having a role in control of oxidative stress and mitochondrial antioxidants that may contribute to cell protection after various injuries
  • mediating activation of MAP3K7/TAK1, leading to the activation of NF Kappa B
  • is essential for the shear stress-stimulated SRC/PTK2/ERK signaling pathway
  • is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
  • has a role in copper metabolism
  • critical controller of apoptotic susceptibility of effector T cell function
  • plays a novel role in endothelial cells and acting as a regulator of vascular antiatherogenic function
  • promoting the binding of STUB1 to the RAF1/Hsp90 complex
  • acting as an E3 ubiquitin ligase for PTEN, promoting Akt activity by regulating PTEN content and compartimentalization
  • critical discriminator between type I and type II apoptosiscritical discriminator between type I and type II apoptosis signalling
  • playing a role in regulating innate immune responses by interacting with NOD1 and NOD2 through interaction with RIPK2
  • protects gangkion cells after axotonomy of the optic nerve, increased intraocular pressure and retinal ischemia ,
  • confers structural neuroprotection of photoreceptors after retinal detachment
  • recruits focal adhesion kinase (PTK2) into integrin-associated focal adhesions, controlling cell migration
  • plays a key role in shear stress-stimulated ERK activation by maintaining the Src-accessible location of PTK2
  • important mediator for the recruitment of PTK2 into the focal adhesion site
  • may play a preventative role in cardiovascular disease
  • its inhibition are essential to limit clonogenicity of Type I tumor cells after TNFSF10 receptor stimulation )
  • negatively regulate GDI1 SUMOylation, which might affect its activity in controlling cell motility
  • has the function of regulating cell motility via regulation of beta-actin polymerization and cytoskeleton formation
  • XIAP, BIRC2, BIRC3 are important regulators of inflammatory processes in endothelial cells
  • plays a key role in vascular functions of PTK2B or PTK2B domain-mediated vascular functions of PTK2
  • is essential for functional activity of PTK2B in endothelial cells
  • regulates a diversity of vascular functions linked to PTK2 and(or) PTK2B
  • potent regulator of innate immune responses
  • co-ordinated development of the brain and face is likely dependent in part upon XIAP mediation of HH/PTCH1-regulated cell survival and apoptosis during embryogenesis
  • XIAP and BIRC2 induce autophagy by upregulating the transcription of BECN1, an essential autophagy gene
  • regulate innate immune signaling
  • plays a key role in the control of mitotic cell death
  • CELLULAR PROCESS cell life, cell death/apoptosis
    cell life, antiapoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • HNRPC 1/2 IRES form are part of a complex modulating BIRC4 expression
  • complexing with BIRC4BP to regulate motoneuron resistance to apoptotic cell death
  • XIAP-CCS complex implicated in apoptosis, copper metabolism, and redox regulation
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • DIABLO (direct IAP binding protein with low pI)
  • TRAF1 and TRAF2
  • COMMD1, a factor recently implicated in copper homeostasis (functioning through COMMD1 to regulate copper homeostasis)
  • MAP3K7IP1 and AIFM1
  • acting cooperatively with BIRC3 and BIRC2 via nonredundant pathways to regulate genotoxic stress-induced nuclear factor-kappaB activation
  • KCNJ6/MAP3K7IP1 interaction is crucial for BIRK4-induced MAP3K7 and NF-kappaB activation
  • RIPK2 via its BIR2 domain, which could be disrupted by XIAP antagonists SMAC and SMAC-mimicking compounds
  • inhibitor of caspase-3, -7 and -9
  • mediates activation of MAP3K7/TAK1, leading to the activation of NF-kappa-B
  • GSPT1/eRF3 protein
  • HtrA2, mammalian homologue of the Escherichia coli heat shock-inducible protein HtrA
  • neurotrophin receptor-interacting MAGE homologue (NRAGE)
  • ILPIP (hILP-Interacting Protein)
  • TAB1-TAK1 receptors
  • XIAP-associated factor 1 (XAF1)
  • survivin (BIRC5)
  • checkpoint kinase Chk1
  • enhances NF-kappaB activity
  • interacts with and ubiquitinates MEKK2
  • binds strongly to C-RAF and promotes the ubiquitylation of C-RAF in vivo through the Hsp90-mediated quality control system
  • interacting with AIFM1 (role for XIAP in regulating cellular reactive oxygen species)
  • caveolin-1 (CAV1)
  • role for XIAP in regulating innate immune responses by interacting with NOD1 and NOD2 through interaction with RIPK2
  • interacting with HAX1, that enhances the stability of XIAP against proteosomal degradation and thus contributing to inhibition of apoptosis
  • regulates actin polymerization and cell motility through its interaction with GDI1
  • VGLL4 triggers a relocalization of XIAP from the cytoplasm to the nucleus
  • interacts with PTK2B, suggesting cross-talk between XIAP and PTK2B
  • interacted with ARHGDIA via its RING domain and negatively modulated ARHGDIA SUMOylation
  • XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2
  • platelets have a functional intrinsic apoptotic-signalling pathway including the pro-apoptotic protease HTRA2 and its target protein XIAP
  • XIAP and, to a lesser extent, BIRC2 were found to directly interact with RHOA independently of the RHOA activation status
  • controls RIPK3-dependent cell death and IL1B secretion in response to TNF, which might contribute to hyperinflammation in patients with XLP2
  • XIAP directly interacts with MAP3K3 and competes with PB1 domain-mediated binding to MAP2K5
  • XIAP is a target for USP11, and stabilization of XIAP due to its deubiquitylation by USP11 leads to the inhibition of cell anoikis and apoptosis, which in turn promotes tumorigenesis
  • cell & other
    REGULATION
    activated by Che-1 in response to DNA damage
    inhibited by SMAC which neutralizes the ability of BIRC4 to repress active caspase 9
    interaction with PRSS25
    AFP
    repressed by S-nitrosylation (does not affect its E3 ligase activity, but instead directly compromising its anticaspase-3 and antiapoptotic function, and contributes to Parkinson disease pathogenesis)
    Phosphorylated by by CDK1-CCNB1 that controls mitotic cell death
    Other
  • degraded by calpain contribution to initiation of apoptosis in neutrophils
  • neutrophils accumulation
  • ubiquitinated and degraded by the proteasome in apoptotic cells
  • phosphorylation by PKB/AKT protects against ubiquitination
  • p34SEI-1 protects the X-linked inhibitor of apoptosis protein (XIAP) from degradation
  • phosphorylated by yclic AMP-dependent protein kinase A (PKA)
  • directly ubiquitinated by TRIM32
    ASSOCIATED DISORDERS
    corresponding disease(s) XLP2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in hepatocellular carcinoma
    tumoral   deletion    
    in X-linked lymphoproliferative syndrome, and in patients with low numbers of natural killer T-lymphocytes (NKT cells)
    constitutional     --low  
    renders cells highly sensitive to oxidative stress
    tumoral     --over  
    in the majority of non-small cell lung carcinoma, together with the abundant or upregulated expression of HBXIP and BIRC5 suggest that tumours are endowed with resistance against a variety of apoptosis-inducing conditions
    tumoral     --over  
    overexpression of FOXM1, XIAP, and BIRC5 contributes to the development of drug-resistance and is associated with poor clinical outcome in breast cancer patients
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerdigestiveliver
    for gene therapy in hepatocellular carcinoma (inhibition of the NF-kappaB/XIAP signaling pathway might selectively abolish the pro-oncogenic activity of TGF-beta1 in advanced hepatocellular carcinomas without affecting the pro-apoptotic effects of TGF-bet
    cancer  
    inhibition as a treatment for malignancy
    cancerdigestivecolon
    targeting CFLAR and BIRC4 may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis
    cardiovascular  
    may be target protein for the prevention of cardiovascular disease
    cancer  
    potential utilization of XIAP as a target for cancer prevention and therapy
    cancerendocrinethyroid
    XIAP inhibitor can be therapeutically targeted, either alone or in combination, to induce efficient apoptosis in PTC with overexpression of XIAP
    ANIMAL & CELL MODELS
    mice deficient in Xiap gene were viable, histopathological analysis did not reveal any differences between IAP-deficient and wild-type mice and any defects in induction of caspase-dependent or -independent apoptosis in cells was found