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FLASH GENE
Symbol APPL1 contributors: mct/pgu - updated : 27-02-2013
HGNC name adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1
HGNC id 24035
Location 3p14.3      Physical location : 57.261.764 - 57.307.496
Synonym name
  • adaptor protein containing pH domain, PTB domain and leucine zipper motif
  • signaling adaptor protein DIP13alpha
  • adaptor molecule interacting with the oncoprotein AKT2
  • DCC-interacting protein 13-alpha
  • Synonym symbol(s) APPA, DIP13alpha, KIAA1428, APPL
    DNA
    TYPE functioning gene
    STRUCTURE 45.74 kb     22 Exon(s)
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    22 - 6061 - 709 - 2008 18455989
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Endocrinepancreas   highly
    Hearing/Equilibriumearinnercochlea highly
    Lymphoid/Immunelymph node   highly
    Nervousbrain    
     spinal cord   highly
    Reproductivefemale systemovary  highly
     male systemprostate   
    Respiratoryrespiratory tracttrachea  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Muscularstriatumskeletal highly
    Nervouscentral   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a PH (pleckstrin homology) domain
  • one PID domain
  • a PTB domain and leucine zipper
  • conjugated PhosphoP
    mono polymer homomer , heteromer , oligo
    HOMOLOGY
    interspecies homolog to murine Appl1 (98.3pc)
    Homologene
    FAMILY
    CATEGORY adaptor , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    text localized in endosomes but also capable of nucleocytoplasmic shuttling
    basic FUNCTION
  • recruiting kinases AKT2 and PIK3 to the cell membrane
  • protein serine/threonine kinase, mediating the DCC apoptotic pathway
  • selectively regulates apoptosis during development by controlling AKT1 signaling
  • may be involved in cell division
  • acting as a critical regulator of the crosstalk between adiponectin signaling and insulin signaling pathways
  • may suppress androgen receptor transactivation via potentiating AKT1 activity
  • mediates AKT1 substrate specificity and cell survival in vertebrate development
  • its overexpression has a proapoptotic effect
  • activator of beta-catenin/TCF-mediated transcription
  • may act as a scaffold that modulated Rab5-associated signaling endosomal membrane by its ability to undergo domain-mediated oligomerizatio, membrane targeting and phosphoinositide binding
  • recruitment of APPL1 to ubiquitin-rich aggresomes in response to proteasomal impairment
  • APPL1 and APPL2 appear to play important roles in cargo trafficking and signal transduction
  • required for EGFR signaling by regulation of EGFR stabilities through inhibition of RAB5A
  • role in regulating cell migration and adhesion turnover through a mechanism that depends on SRC and AKT1
  • positive regulator of transcriptional activity of NFKB under basal but not TNF-stimulated conditions
  • APPL1 synergized with TRAF2 to induce NFKB activation, and both proteins were necessary for this process and function upstream of the IKK complex
  • plays a critical role in regulating adiponectin and insulin signaling
  • CELLULAR PROCESS cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    intracellular signaling cascade
    a component
  • associating with the nuclear co-repressor complex NuRD, containing enzymatically acitve HDAC2
  • APPL1, an interacting partner of AKT1, forms complexes with CDON and BOC in differentiating myoblasts
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binding to the oncoprotein AKT2 and PI3 kinase catalytic subunit p110alpha
  • binding to DCC
  • interacting with SSNA1
  • interacts with adiponectin receptors and the interaction is stimulated by adiponectin
  • interacts with transmembrane receptors and AKT1
  • binding partner for the NTRK1-interacting protein GIPC1
  • interacting with GIPC1 (GIPC1 and APPL1 play a role in NTRK1 function and suggest that a population of endosomes bearing a complex of APPL1, GIPC1, and activated NTRK1 may transmit NGF signals)
  • binding to RAB5A
  • directly interact with TRAF2, an adaptor protein known to activate canonical NFKB signaling
  • function as a downstream effector of EGF-initiated signaling
  • TRAF6-mediated ubiquitination of APPL1 is a vital step for the hepatic actions of insulin through modulation of membrane trafficking and activity of AKT1
  • cell & other
    REGULATION
    Phosphorylated by PRKCA (PRKCA is the kinase mediating ER stress-induced phosphorylation of APPL1 at Ser(430)
    Other phosphorylated by ATM or ATR
    cellular levels of HDAC1 can regulate the extent of APPL1-NuRD interaction which in turn regulates the nucleoplasmic distribution of APPL1
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    caused developmental delay and with high penetrance a number of dysmorphic phenotypes, such as severely swollen yolk extension, slightly swollen telencephalon, blown-up blood island and, later in development, sharp kinks in body axes
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    good candidate to target for the treatment of cancers caused by dysregulation of EGF signaling
    cancer  
    regulatory function of APPL1 on Akt signaling and its mediated substrate specificity discovered here may therefore render APPL1 a particularly interesting target for cancer therapy
    ANIMAL & CELL MODELS