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FLASH GENE
Symbol TOLLIP contributors: mct/pgu - updated : 26-09-2018
HGNC name toll interacting protein
HGNC id 16476
Location 11p15.5      Physical location : 1.295.597 - 1.330.892
Synonym name
  • Toll-interacting protein
  • adapter protein
  • Synonym symbol(s) IL-1RAcPIP, FLJ33531
    DNA
    TYPE functioning gene
    STRUCTURE 35.29 kb     6 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    RPLP2 5q31 ribosomal protein, large P2 TTS-2.2 11p15.5 transport-secretion protein 2.2 MGC45840 11p15.5 hypothetical protein MGC45840 CD151 11p15.5 CD151 antigen POLR2L 11p15 polymerase (RNA) II (DNA directed) polypeptide L, 7.6kDa TM4SF7 11p15.5 transmembrane 4 superfamily member 7 MGC3234 11p15.5 hypothetical protein MGC3234 AP2A2 11p15.5 adaptor-related protein complex 2, alpha 2 subunit MUC6 11p15.5 mucin 6, gastric LOC387738 11 similar to secreted gel-forming mucin LOC338731 11p15.5 hypothetical LOC338731 LOC387739 11 LOC387739 LOC387740 11 similar to Mucin 2 precursor (Intestinal mucin 2) MUC5B 11p15.5 mucin 5, subtype B, tracheobronchial TOLLIP 11p15.5 toll interacting protein STK29 11p15.5 serine/threonine kinase 29 HCCA2 11p15.5 HCCA2 protein DUSP8 11p15.5 dual specificity phosphatase 8
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    6 - 3665 - 274 - 2000 10854325
    5 - 3515 - 224 - 2000 10854325
    3 - 3238 - 80 - 2000 10854325
    5 - 3482 - 213 - 2000 10854325
    6 - 3675 - 205 - 2000 10854325
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinelarge intestinecolon highly Homo sapiens
    Lymphoid/Immunespleen   highly
    Nervousbrain   highly
    Reproductivefemale systemplacenta    Homo sapiens
    Skin/Tegumentskin   highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveepithelial cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a conserved C2 domain, an endosome anchoring domain, preferentially interacting with phosphoinositides, most notably with PtdIns3P (phosphatidylinositol 3-phosphate) and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate), in a Ca2+-independent manner
  • a TOM1 binding domain (TBD) that is involved in the interaction with TOM1, a protein that binds ubiquitinated proteins
  • a CUB domain, potentially involved in binding ubiquitin conjugating enzymes
  • a CUE (coupling of ubiquitin to endoplasmic reticulum degradation) domain in the C terminus, and this domain functions as an interaction motif for ubiquitinated proteins
  • HOMOLOGY
    Homologene
    FAMILY
  • TOLLIP family
  • CATEGORY adaptor
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm,nuclear bodies
    text
  • basic residues of the C2 domain mediate membrane targeting of TOLLIP by interaction with phosphoinositides, which contribute to the observed partition of the protein in different subcellular compartments
  • was mainly located in the cytoplasm of cytotrophoblasts in the first-trimester placental tissues
  • basic FUNCTION
  • inhibiting IRAK1 activity
  • inhibits cell activation by microbial products
  • required for sorting of IL1RI at late endosomes
  • functions as an endosomal adaptor linking IL1RI, via TOM1, to the endosomal degradation machinery
  • modulates IRAK function in the TLR signalling pathway
  • negative regulator of Toll-like receptor signaling
  • spatial expression of TOLLIP at different stages of gestation may play an important role in the pathophysiology of preeclampsia (PE)
  • modulates intracellular trafficking and degradation of TGFB receptors
  • is a critical regulator of the Toll-like receptor-mediated signalling pathway
  • acts as a novel modulator of ischaemia-reperfusion (I/R) injury by promoting neuronal apoptosis and ischaemic inflammation, which are largely mediated by suppression of AKT1 signalling
  • TOLLIP-mediated inhibition of WNT signaling may contribute not only to embryonic development, but also to carcinogenesis
  • can potentially coordinate multiple cellular pathways of trafficking and signaling, possibly by exploiting its ability to interact with ubiquitin and the sumoylation machinery
  • is a key negative regulator of innate immunity by preventing excessive proinflammatory responses
  • TOLLIP protects against neointima formation by negatively regulating vascular smooth muscle cell proliferation, dedifferentiation, and migration in an AKT1-dependent manner
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
  • TLR and IL1-R signaling pathways
  • TOLLIP is a novel modulator of TGFB signaling pathway
  • a component
  • complexing with IRAK1 in unstimulated cells
  • form a complex with TOM1 and regulate endosomal trafficking of ubiquitinated proteins
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binding to TLR2 and TLR4
  • binding to IL1RAP
  • interacts with IL1R1
  • interacting specifically with TOM1 and TOM1L1
  • interacting with RCAN1 (RCAN1-1S isoform positively modulates IL-1R-mediated signaling pathways by regulating TOLLIP/IRAK1/TRAF6 complex formation)
  • ELF1 is a transcription factor that negatively regulates TOLLIP gene expression
  • interacts with SMAD7, a major modulatory protein involved in the negative regulation of TGFB signaling
  • TOLLIP cooperates with SMAD7 to modulate intracellular trafficking and degradation of ubiquitinated TGFBR1, whereby negatively regulates TGFB signaling pathway
  • TOLLIP binds ubiquitin through its C2 and CUE domains and that its association with the C2 domain inhibits PtdIns(3)P binding
  • attenuates TGFB-induced epithelial-mesenchymal transition
  • EZH1 promotes TLR-triggered inflammatory cytokine production by suppressing the TLR negative regulator TOLLIP, contributing to full activation of the innate immune response against invading pathogens
  • critical role of TOLLIP in the early phase of TLR4-mediated neuroinflammation
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    selectively leads to enlarged yet stable atherosclerotic plaques, increased circulating lipids, liver steatosis, and reduced inflammation
    constitutional     --low  
    in human failing hearts
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cardiovascularaquired 
    upregulation of TOLLIP may be a promising strategy for treating vascular remodeling-related diseases
    neurologyneurodegenerativeParkinson/dementia Parkinsonism
    may be a potential target for neuroprotection
    ANIMAL & CELL MODELS
  • global Tollip-knockout mouse model revealed an aggravated cardiac hypertrophy and accelerated maladaptation to chronic pressure overloading