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FLASH GENE
Symbol APPL1 contributors: mct/pgu - updated : 17-05-2017
HGNC name adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1
HGNC id 24035
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • multiple functional domains, including a Bin1/amphiphysin/rvs167 (BAR) domain,
  • a pleckstrin homology (PH) domain, and a phosphotyrosine binding (PTB) domain
  • one PID domain
  • a 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,vesicle
    intracellular,nucleus
    text
  • localized in endosomes but also capable of nucleocytoplasmic shuttling
  • resides on a tubulo-vesicular compartment that is capable of sorting cargo for recycling or degradation and that displays long lifetimes, all features typical of early endosomes
    • 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
  • obligatory role of APPL1 in insulin secretion
  • role of APPL1 as a key regulator that couples insulin signaling to insulin secretion in beta cells
  • 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
  • important mediator of insulin and adiponectin signaling
  • APPL1 sensitizes insulin signaling by acting at a site downstream of the INSR
  • critical role of APPL1 in glucose homeostasis
  • APPL1 endosomes represent a distinct population of RAB5-positive sorting endosomes, thus providing important insights into the compartmental organization of the early endocytic pathway
  • plays a critical role in regulating adiponectin and insulin signaling pathways
  • negatively regulates inflammation and apoptosis in pancreatic beta cells
    • 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
  • function as a downstream effector of EGF-initiated signaling
  • couples insulin-stimulated AKT1 activation to glucose-stimulated insulin secretion by promoting the expression of the core exocytotic machinery involved in exocytosis
  • directly interact with TRAF2, an adaptor protein known to activate canonical NFKB 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
  • APPL1 is a critical molecule that promotes IRS1/2-INSR interaction
  • role of APPL1 as a positive regulator of DVL2-dependent transcriptional activity of JUN
  • binds to AKT2, a key molecule in the insulin signaling pathway, thereby enhancing insulin-induced AKT2 activation and downstream signaling leading to insulin action and secretion
  • APPL1 and APPL2 are associated with TGFBR1 in a TRAF6-dependent manner
  • in response to mechanical stretch, APPL1 enhances glucose uptake by modulating the activation and localization of PRKCZ, as well as its functional interaction with both PPP2CA and MYO2A
  • positively mediated leptin signaling and promoted leptin-induced proliferation and migration of cancer cells
    • 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) MODY14
    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
    constitutional germinal mutation     loss of function
    in familial diabetes mellitus
    tumoral     --over  
    in aggressive prostate cancer tissues
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
  • APPL, APPL2-TGFBR1 complex may serve as a prognostic marker, in prostate cancer
    • 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
    diabete  
    potential target for future treatments aimed at preserving or restoring glucose homeostasis
    diabetetype 1 
    promising target for treating type 1 diabetes
    diabete  
    may be a new therapy target for diabetic nephropathy
    ANIMAL & CELL MODELS
  • Appl1 Tg mice exhibit improved peripheral metabolism, reduced cardiac lipotoxicity, and improved insulin sensitivity
  • Appl1 knockout mice exhibit glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS)