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FLASH GENE
Symbol RIPK1 contributors: mct/shn - updated : 28-04-2017
HGNC name receptor (TNFRSF)-interacting serine-threonine kinase 1
HGNC id 10019
Location 6p25.2      Physical location : 3.077.057 - 3.115.419
Synonym name
  • receptor interacting protein
  • death domain kinase
  • RIP1 kinase
  • cell death protein RIP
    • Synonym symbol(s) FLJ39204, RIP, RIP1
    EC.number 2.7.11.1
    DNA
    TYPE functioning gene
    STRUCTURE 51.30 kb     11 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Map pter - D6S1600 - D6S344 - RIPK1 - D6S1617 - D6S1617 - cen
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    11 - 3864 - 671 - 2007 17235653
    13 - 4374 - 508 - 2007 17235653
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveesophagus   highly
     intestinesmall intestine   
    Nervousbrain    
    Reproductivefemale systemplacenta    Homo sapiens
    Urinarybladder   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
         
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal region with homology to protein kinases, and a Ser/Thr kinase domains (KDs)
  • an intermediate domain of RIPK1 harbors an anti-apoptotic function, with a RHIM domain
  • a C terminal region containing a DEATH domain, and a unique homotypic interaction motif at the C terminus of both RIPK1 and RIPK3 that is required for their association , and also for recruitment to the TNF receptor signaling complex
    • conjugated PhosphoP
    HOMOLOGY
    interspecies ortholog to Ripk1, Mus musculus
    ortholog to Ripk1, Rattus norvegicus
    ortholog to RIPK1, Pan troglodytes
    Homologene
    FAMILY
  • protein kinase superfamily
  • TKL Ser/Thr protein kinase family
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    text
  • present both in the cytoplasm and in the nucleus
  • SIRT2 and RIPK1 are identified in the cytotrophoblast cytoplasm
    • basic FUNCTION
  • dual-function molecule that can be either prosurvival or prodeath depending on its ubiquitination state, and this serves as an NF-kappaB-independent cell-death switch early in TNF signaling
  • playing an important role for DNA damage-induced, TP53-independent cell death
  • one of the critical components involved in mediating DNA damage-induced, TP53-independent cell death
  • one of the major components of the tumor necrosis factor receptor 1 complex and plays an essential role in tumor necrosis factor-mediated nuclear factor kappaB activation (
  • plays a critical role in tumor necrosis factor-alpha (TNF)-induced IkappaB kinase (IKK) activation and subsequent activation of transcription factor NF-kappaB
  • inhibiting the expression of the epidermal growth factor receptor (EGFR)
  • crucial modulator of epidermal differentiation, and important and unique functions in keratinocytes of normal and wounded skin
  • critical mediator of inflammation and stress-induced NF-kappaB activation, regulates the expression of the epidermal growth factor receptor (EGFR)
  • downregulates EGFR expression by interfering with the function of Sp1, which is a key activator of EGFR transcription
  • specifically recruited to the TNFalpha receptor in the activation of necroptosis
  • required for death receptor agonists to activate necrosis
  • RIPK1 and RIPK3 are key signaling molecules in necrosis and are regulated by caspases and ubiquitination
  • required for CD40 ligand-induced caspase-8 activation and tumor cell killing
  • RIPK1 and caspase-8 were recruited to the DDX58 complex after viral infection and served antagonistic regulatory roles
  • regulates embryogenesis and lymphocyte responses (
  • a IKBKG- and RIPK1-based switch mechanism involving TNF-TNFR1 feedforward signaling that mediates ATM-induced cytokine secretion and caspase activation selectively in the context of severe DNA damage
  • is a central kinase in TNFR1 signaling participating in NFKB activation, necroptosis, and apoptosis
  • functions as a platform mediating survival signals and as an active kinase during necroptosis and apoptosis in the presence of Smac mimetics
  • RIPK1, RIPK3 are central players in TNF-induced programmed necrosis
  • key switch of cell fate regulation
  • necroptosis is controlled by the action of two serine/threonine kinases, RIPK1 and RIPK3
  • RIPK1 blocks early postnatal lethality mediated by CASP8 and RIPK3
  • RIPK1 can activate RIPK3 in response to receptor signaling, but also acts as a negative regulator of spontaneous RIPK3 activation in the cytosol
  • is essential for survival of intestinal epithelial cells (IECs), ensuring epithelial homeostasis by protecting the epithelium from CASP8-mediated IEC apoptosis independently of its kinase activity and NFKB1 activation
  • RIPK1 is dispensable for necroptosis and can act as an inhibitor of this process
  • key player in inflammation and cell death, that assumes opposite functions depending on the cellular context and its posttranslational modifications
  • is essential for the regulation of death receptor mediated autophagy and apoptosis
  • RIPK1 and RIPK3 directly regulate inflammatory signaling, which complicates interpretation of their function but might alter their therapeutic utility
  • RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration
  • RIPK1 regulates cell death and inflammation through kinase-dependent and -independent functions
  • inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers
  • enzyme acting downstream of tumor necrosis factor alpha to control cell survival and death
  • is an essential downstream component of many pattern recognition and death receptors
  • cell-death- and inflammation-independent function of RIPK1 and CASP8, promoting faithful chromosome alignment in mitosis and thereby ensuring genome stability
    • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
  • interacting with IKBKG and modulatory NF-kappa B activation and apoptosis
  • necroptosis is a RIPK1-dependent programmed cell death (PCD) pathway that is distinct from apoptosis
    • a component
  • RIPK1 and RIPK3 form an amyloid structure through their RHIMs and that this heterodimeric amyloid structure is a functional signaling complex that mediates programmed necrosis
  • RIPK1 also formed a complex with VDR, and RIPK1 increased VDR retention in the cytoplasm, which may account for its inhibition of VDR transcriptional activity
    • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP
    • protein
  • Fas/APO-1 (CD95) (
  • TNFRSF1A-associated via death domain, TRADD (
  • FADD/MORT1 (
  • Death receptor 4, DR4 and Death receptor 5, DR5 (
  • TNFRSF1A
  • aPKC-binding protein, p62 (
  • heat shock protein 90, Hsp90 (
  • NEMO (IKKgamma) (
  • epidermal growth factor receptor, EGFR (
  • IKBKG and modulatory NF6kappa B activation and apoptosis
  • RIPK3
  • zinc finger protein inhibiting NF-kappa B (
  • Focal adhesion kinase, FAK (
  • RNF216 (E3 ubiquitin-protein ligase to RIPK1 and Hsp90 and RNF216 cooperatively maintain the homeostasis of RIPK1
  • cylindromatosis (turban tumor syndrome), CYLD (
  • CSNK1A1
  • TAK1 kinase (
  • ZBP1 recruits RIPK1 and RIPK3 through RIP homotypic interaction motifs to activate NF-kappaB
  • ubiquitin specific peptidase 21, USP21
  • links the immunoregulatory CD40 receptor to apoptotic signaling in carcinomas
  • RIPK1
  • CD40 (
  • interacting with ATM (in the context of excessive DNA damage, ATM employs IKBKG and RIPK1 through autocrine TNF signaling to switch on cytokine production and caspase activation)
  • FCMR regulates the balance between apoptotic and nonapoptotic death receptor signaling by facilitating RIPK1 ubiquitination
  • PGAM5 is a kinase substrate of RIPK1/RIPK3
  • necroptosis depends on the kinases RIPK1 and RIPK3, which interact through their RHIM domains to form the necrosome
  • recruitment of IKBKG to ubiquitinated RIPK1 is a key step in the TNFR1 signaling pathway that determines whether RIPK1 triggers a necrotic death response
  • RIPK1 is a critical target of SIRT2-dependent deacetylation
  • AKT1 activity, mediated in part through MTOR, links RIPK1 to JNK activation and autocrine production of TNF
  • likely TNF-induced necroptosis is tightly associated with oxidative stress, and oxidative stress is induced downstream of RIPK1 activation
  • PELI3 targets RIPK1, in a TNF-dependent manner, to inhibit TNF-induced complex II formation
  • TRADD is an adapter molecule that bridges the interaction between TNFRSF1A and receptor-interacting serine/threonine-protein kinase 1 (RIPK1)
  • intrinsically suppresses spontaneous RIPK3 activation in the cytosol by controlling RIPK3 oligomerization
  • regulates hematopoiesis and prevents inflammation by suppressing RIPK3 activation
  • indirectly regulates likely CASP8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (ERN1)
  • ZFP36 promotes the assembly of the death complex called Ripoptosome and induces RIPK1-dependent death
  • RHIM motif of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development
  • unexpected roles for RIPK1 and RIPK3 kinases in the production of IFNB1 during the host inflammatory responses to bacterial infection, suggesting that the axis in which these kinases operate may represent a target for bacterial virulence factors
  • ubiquitination of RIPK1 by PELI1 promotes the formation of necrosome and execution of necroptosis
  • functions as a key mediator of tissue homeostasis via formation of CASP8 activating ripoptosome complexes, positively and negatively regulating apoptosis, necroptosis, and inflammation
  • PLK1 is recruited into mitotic ripoptosomes, where PLK1's activity is controlled via RIPK1-dependent recruitment and CASP8-mediated cleavage
  • TRADD plays a more dominating role in NFKB1-signaling than RIPK1
  • HTRA2 directly interacted with RIPK1 and promoted its degradation during a specific time phase of necroptosis
    • cell & other
    REGULATION
    Other regulated by TRADD
    negatively regulated by RNF11 (
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in glomerulus and tubule of class III and IV lupus nephritis
    constitutional     --over  
    in preeclampsia (PE) placenta
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • RIP-deficient mice appear normal at birth but fail to thrive, displaying extensive apoptosis in both the lymphoid and adipose tissue and dying at 1-3 days of age (
  • mice lacking Ripk1 in intestinal epithelial cells (IECs) spontaneously develop severe intestinal inflammation associated with IEC apoptosis leading to early death
  • RIP1 deficiency allowed normal embryogenesis of Fadd(-/-) mice and the developmental defect of Rip1(-/-) lymphocytes was partially corrected by FADD deletion (
  • Fadd(-/-)Rip1(-/-) double-knockout T cells are resistant to death induced by Fas or TNF-&
    • 945; and show reduced NF-&
    954;B activity (