Affinage

APPL1

DCC-interacting protein 13-alpha · UniProt Q9UKG1

Length
709 aa
Mass
79.7 kDa
Annotated
2026-04-28
100 papers in source corpus 52 papers cited in narrative 52 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

APPL1 is a multifunctional endosomal adaptor protein that links receptor internalization to intracellular signaling and transcriptional regulation across diverse cell types. Its BAR-PH domain forms a crescent-shaped dimer that binds Rab5/Rab21 via a novel β-strand contact mode and targets APPL1 to a PI3P-sensitive subpopulation of early endosomes that constitute a distinct sorting compartment preceding classical EEA1-positive endosomes (PMID:17581628, PMID:19303853, PMID:26459602). Through its PTB domain, APPL1 scaffolds inactive Akt with receptors (adiponectin receptors, insulin receptor, TrkA/B, FSHR, NMDAR, mPRβ), competing with the Akt inhibitor TRB3 and facilitating TRAF6-mediated Lys63-ubiquitination at Lys160 for membrane targeting; it also scaffolds the TAK1–MKK3–p38 and LKB1–AMPK cascades downstream of adiponectin, recruits OCRL/Inpp5B to phagosomes for PI(4,5)P2 turnover, promotes early-endosome-dependent mitophagy that restricts NLRP3 inflammasome activation, and translocates to the nucleus to modulate β-catenin/TCF transcription and NF-κB signaling via NuRD/HDAC complex interactions (PMID:16622416, PMID:19416712, PMID:23909487, PMID:20978232, PMID:19520843, PMID:22072788, PMID:34789781, PMID:19433865, PMID:22685329). Loss-of-function mutations in APPL1 (p.Leu552* and p.Asp94Asn) cause familial diabetes through impaired insulin-stimulated AKT2 activation (PMID:26073777).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    The initial identification of APPL1 as a direct Akt2 and PI3Kα-binding partner established it as a potential scaffold linking PI3K signaling to Akt, raising the question of where and how it operates.

    Evidence Yeast two-hybrid screen with co-immunoprecipitation and GST pulldown validation

    PMID:10490823

    Open questions at the time
    • No cellular localization determined
    • Functional consequence of Akt2 binding not tested
    • Upstream signals triggering the interaction unknown
  2. 2004 High

    Discovery that APPL1 resides on Rab5-positive endosomes and translocates to the nucleus upon growth factor or stress stimulation to engage the NuRD/HDAC complex established the endosome-to-nucleus signaling paradigm for APPL1.

    Evidence Co-immunoprecipitation, subcellular fractionation, live imaging, and mass spectrometry in mammalian cells

    PMID:15016378

    Open questions at the time
    • Nuclear target genes not identified
    • Mechanism of nuclear translocation signal unknown
    • Physiological relevance of NuRD interaction not yet demonstrated in vivo
  3. 2006 High

    Identification of APPL1 as a direct adaptor for adiponectin receptors and for TrkA/GIPC1 complexes broadened its role from a generic Akt scaffold to a receptor-proximal signaling node coupling multiple transmembrane receptors to endosomal Akt, AMPK, and MAPK pathways.

    Evidence Yeast two-hybrid, reciprocal co-immunoprecipitation, siRNA knockdown, MS identification, and functional assays (glucose uptake, neurite outgrowth) in adipocytes, myocytes, and PC12 cells

    PMID:16622416 PMID:17000777 PMID:17015470

    Open questions at the time
    • Whether APPL1 directly activates Akt or merely scaffolds it was unresolved
    • Structural basis of receptor binding unknown
    • Receptor selectivity mechanism unclear
  4. 2007 High

    Crystal structures of the APPL1 BAR-PH and PTB domains revealed a novel four-helical-bundle BAR dimer with PH domains at distal ends that directly contact Rab5/Rab21 via β-strands, providing the structural basis for endosomal membrane targeting and explaining how APPL1 senses membrane curvature.

    Evidence X-ray crystallography with mutagenesis and biochemical binding validation

    PMID:17502098 PMID:17581628

    Open questions at the time
    • No full-length structure available
    • How phospholipid binding by all three domains is coordinated unclear
    • Structure of APPL1 bound to receptors not resolved
  5. 2008 High

    In vivo genetic evidence from zebrafish demonstrated that APPL1 endosomes confer substrate selectivity on Akt, promoting GSK-3β but not TSC2 phosphorylation, establishing that endosomal localization dictates signaling output rather than merely serving as a passive platform.

    Evidence Zebrafish loss-of-function genetics with epistasis analysis, live imaging, and co-immunoprecipitation

    PMID:18455989

    Open questions at the time
    • Mechanism of substrate selectivity at endosomal membranes unknown
    • Whether this selectivity is conserved in mammals was untested
    • How APPL1 excludes TSC2 unclear
  6. 2009 High

    A series of studies established the molecular logic of APPL1 endosomal identity: PI3P acts as a biochemical switch converting APPL1 endosomes to EEA1 endosomes, APPL1 competes with TRB3 to release Akt for membrane translocation, APPL1 scaffolds LKB1 for AMPK activation, and APPL1 activates β-catenin/TCF transcription by relieving Reptin/HDAC repression.

    Evidence Quantitative live imaging with acute PI3P manipulation; competitive binding assays with in vivo rescue in db/db mice; LKB1 cytosolic translocation assays; reporter assays and ChIP for β-catenin targets

    PMID:19303853 PMID:19416712 PMID:19433865 PMID:19520843 PMID:19661063 PMID:19686092

    Open questions at the time
    • How PI3P production is temporally controlled on APPL endosomes unresolved
    • Whether TRB3 competition occurs in all tissue contexts untested
    • Transcriptional targets downstream of APPL1 nuclear activity not comprehensively mapped
  7. 2011 High

    APPL1 was shown to scaffold TAK1-MKK3-p38 signaling downstream of adiponectin, recruit OCRL/Inpp5B to phagosomes for PI(4,5)P2 clearance, regulate synapse formation via Akt-PAK, stabilize NIK to activate basal NF-κB, and link FSHR to IP3/Ca²⁺ signaling—demonstrating its function as a versatile signaling hub across innate immunity, neuronal, endocrine, and metabolic contexts.

    Evidence In vitro binding and scaffolding assays; siRNA knockdown with phosphoinositide detection on phagosomes; neuronal spine analysis with domain deletions and kinase inhibitors; TRAF2 interaction with NIK stabilization assays; FSHR alanine-scanning mutagenesis with IP3/Ca²⁺ imaging

    PMID:20978232 PMID:21236345 PMID:21285318 PMID:22072788 PMID:22685329

    Open questions at the time
    • Whether the different scaffolding functions are mutually exclusive or concurrent unknown
    • How APPL1 simultaneously interacts with such diverse partners given domain overlap unclear
    • Stoichiometry of multivalent complexes not determined
  8. 2012 High

    Identification of TRAF6-mediated Lys63-ubiquitination at K160 as essential for APPL1 membrane targeting and Akt activation, and PKCα-dependent Ser430 phosphorylation as a brake causing ER-stress-induced insulin resistance, revealed how post-translational modifications switch APPL1 between active and inhibited states.

    Evidence Site-directed mutagenesis (K160R, S430D/A), ubiquitination assays, kinase assays, adenoviral rescue in obese mice, hepatocyte signaling

    PMID:22685300 PMID:23909487

    Open questions at the time
    • Whether other E3 ligases can ubiquitinate APPL1 unknown
    • Deubiquitinase that reverses K160 ubiquitination not identified
    • Interplay between S430 phosphorylation and K160 ubiquitination not tested
  9. 2014 High

    APPL1 knockout mice showed systemic insulin resistance due to selectively impaired IRS1/2 tyrosine phosphorylation, and human whole-exome sequencing identified APPL1 loss-of-function mutations (p.Leu552* and p.Asp94Asn) in familial diabetes, providing definitive genetic proof that APPL1 is required for physiological insulin signaling.

    Evidence APPL1 KO mice with metabolic phenotyping; human exome sequencing with functional validation of mutations in HepG2 cells

    PMID:24813896 PMID:26073777

    Open questions at the time
    • Penetrance and prevalence of APPL1 mutations in broader diabetic populations unknown
    • Whether the D94N mutation affects BAR domain structure not structurally resolved
    • Tissue-specific contributions to diabetes phenotype not dissected
  10. 2017 High

    PKA-dependent phosphorylation of APPL1 at Ser410 was identified as the mechanism controlling GPCR recycling from very early endosomes, linking Gαs/cAMP signaling to APPL1-dependent receptor trafficking.

    Evidence siRNA knockdown, FRET-based cAMP biosensor, receptor recycling assay, phosphorylation mapping for LHR in HEK293 cells

    PMID:29212031

    Open questions at the time
    • Whether S410 phosphorylation regulates non-GPCR cargo recycling unknown
    • Phosphatase that reverses S410 not identified
    • Generalizability to other Gαs-coupled GPCRs not shown
  11. 2019 High

    APPL1 endosomes were found to mediate retrograde axonal transport of TrkB and Akt1 in hippocampal neurons, and dynamin-1/mutant-p53 was shown to stabilize APPL1 on peripheral endosomes to create a positive feedback loop promoting integrin recycling and cancer cell migration.

    Evidence Live-cell imaging with FRET in primary neurons; siRNA with integrin recycling assays and focal adhesion dynamics in cancer cells

    PMID:30792402 PMID:31043431

    Open questions at the time
    • Cargo selectivity of retrograde APPL1 endosomes beyond TrkB/Akt1 not characterized
    • Whether the dynamin-1 feedback loop operates in non-cancer contexts unclear
    • Motor proteins driving retrograde APPL1 endosome movement not identified
  12. 2021 High

    APPL1 was established as a critical mediator of early-endosome-dependent mitophagy that restricts NLRP3 inflammasome activation, revealing an unexpected role in innate immune homeostasis whereby APPL1 translocates from endosomes to damaged mitochondria to promote their clearance.

    Evidence Hematopoietic-specific APPL1 KO mice, mitophagy assays, NLRP3 inflammasome activation assays, live imaging in macrophages

    PMID:34789781

    Open questions at the time
    • Mechanism of APPL1 translocation from endosomes to mitochondria not resolved
    • Whether Rab5 on mitochondria represents endosome-mitochondria contact sites or fusion events unclear
    • Relevance to other inflammasomes not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how APPL1 coordinates its simultaneous roles as endosomal scaffold, nuclear shuttling adaptor, and mitophagy mediator; what determines receptor and cargo selectivity at APPL1 endosomes; and the full spectrum of transcriptional targets regulated by nuclear APPL1.
  • No full-length APPL1 structure in complex with any receptor
  • Comprehensive interactome under different signaling conditions not available
  • Tissue-specific versus universal functions not systematically dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 3
Localization
GO:0005768 endosome 8 GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-1430728 Metabolism 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 1
Partners
ADIPOR1ADIPOR2AKT2GIPC1NTRK1OCRLRAB5ATRAF6
Complex memberships
APPL1-APPL2 heterodimerAdipoR1/2-APPL1 signaling complexNuRD/MeCP1 complex

Evidence

Reading pass · 52 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 APPL1 was identified as a direct binding partner of adiponectin receptors AdipoR1 and AdipoR2 via its PTB domain interacting with the intracellular region of the receptors; this interaction is stimulated by adiponectin and mediates downstream signaling including lipid oxidation, glucose uptake, and GLUT4 membrane translocation. APPL1 also stimulates Rab5 interaction upon adiponectin treatment to increase GLUT4 translocation. Yeast two-hybrid screen, co-immunoprecipitation, siRNA knockdown, overexpression assays in mammalian cells Nature cell biology High 16622416
2004 APPL1 and APPL2 are Rab5 effectors residing on a subpopulation of endosomes; in response to EGF or oxidative stress, APPL1 translocates from endosomal membranes to the nucleus where it interacts with the NuRD/MeCP1 nucleosome remodeling and histone deacetylase complex, thereby linking endosomal signaling to gene expression and cell proliferation. Co-immunoprecipitation, subcellular fractionation, live imaging, RNAi knockdown, mass spectrometry Cell High 15016378
2009 APPL endosomes represent an early endocytic intermediate derived from clathrin-coated vesicles and macropinosomes; PI3P acts as a switch to convert APPL endosomes into classical Rab5/PI3P-positive endosomes, and depletion of PI3P causes reversion of Rab5-positive endosomes to the APPL stage and enhances growth factor signaling. Quantitative single vesicle live imaging, acute pharmacological manipulation of PI3P, PI3P depletion experiments Cell High 19303853
2008 In zebrafish, Appl1 regulates Akt activity and substrate specificity from endosomes: it controls GSK-3β phosphorylation but not TSC2, selectively promoting cell survival. Akt and GSK-3β, but not TSC2, dynamically associate with Appl1 endosomes upon growth factor stimulation, and Appl1 function requires its endosomal localization. Zebrafish loss-of-function genetics, live imaging, epistasis analysis, co-immunoprecipitation Cell High 18455989
1999 APPL1 was identified as a direct binding partner of AKT2 kinase and of the PI3K catalytic subunit p110α; APPL1 preferentially interacts with the inactive form of AKT2, suggesting it may tether inactive AKT2 to p110α in the cytoplasm. Yeast two-hybrid screen, co-immunoprecipitation, GST pulldown Oncogene High 10490823
2007 Crystal structure of the human APPL1 N-terminal BAR-PH domain revealed a crescent-shaped symmetrical dimer with a novel linker helix integrating BAR and PH domains; biochemical analyses identified two independent Rab5-binding sites at opposite ends of the dimer where the PH domain directly contacts Rab5 and Rab21 using β-strands, a new binding mode between PH domains and small GTPases. X-ray crystallography, biochemical binding assays, mutagenesis The EMBO journal High 17581628
2007 Crystal structures of the APPL1 BAR-PH and PTB domains revealed a novel BAR domain dimer with two four-helical bundles (unlike the three-helix bundles of other BAR domains), PH domain located at opposite ends of the BAR dimer, and confirmed that BAR, PH, and PTB domains can all bind phospholipids. X-ray crystallography, yeast two-hybrid, lipid binding assays Structure High 17502098
2007 APPL1 mediates adiponectin-induced eNOS phosphorylation at Ser1177 and NO production in endothelial cells via AdipoR1/2; APPL1 knockdown attenuates adiponectin-induced AMPK phosphorylation and eNOS/HSP90 complex formation, while constitutively active AMPK rescues these effects. Proteomic analysis, RNA interference, adenoviral overexpression, co-immunoprecipitation Diabetes High 17287464
2009 In muscle cells, adiponectin and metformin promote APPL1-dependent LKB1 cytosolic translocation: APPL1 directly interacts with adiponectin receptors and anchors LKB1 in the cytosol, thereby activating AMPK. A secondary pathway involving PLC/Ca2+/CaMKK also contributes. Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, overexpression in C2C12 cells The Journal of biological chemistry High 19520843
2009 APPL1 potentiates insulin-mediated suppression of hepatic gluconeogenesis by binding Akt and blocking its interaction with the endogenous inhibitor TRB3 through direct competition, thereby promoting Akt translocation to the plasma membrane and endosomes for further activation. Co-immunoprecipitation, competitive binding assay, APPL1 knockdown/overexpression, adenoviral gene delivery in db/db mice Cell metabolism High 19416712
2006 APPL1 associates with the neurotrophin receptor TrkA through two routes: its PTB domain binds TrkA directly, and its C-terminus binds the PDZ domain of GIPC1 which also binds TrkA. APPL1, GIPC1, and phosphorylated TrkA co-fractionate in endosomal fractions. APPL1 knockdown suppresses NGF-dependent MEK, ERK, and Akt activation and neurite outgrowth. Mass spectrometry, co-immunoprecipitation, high-resolution centrifugation fractionation, siRNA knockdown, PC12 cell differentiation assay Molecular and cellular biology High 17000777
2006 Endogenous GIPC binds the C-terminus of APPL1; upon TrkA activation by NGF, GIPC and APPL1 translocate to incoming TrkA-bearing endocytic vesicles at cell process tips. APPL1 interaction via the GIPC PDZ domain is essential for recruitment of GIPC to peripheral endosomes and for TrkA signaling (MAPK activation and neurite outgrowth); GIPC is required for efficient TrkA endocytosis and trafficking. Co-immunoprecipitation, siRNA knockdown, live imaging, endosome fractionation Molecular and cellular biology High 17015470
2007 APPL1 forms a complex with Akt2 in primary rat adipocytes and skeletal muscle under basal conditions; this complex dissociates upon insulin stimulation. APPL1 knockdown suppresses Akt phosphorylation, glucose uptake, and GLUT4 translocation in adipocytes, and APPL1 partially co-localizes with GLUT4. Co-immunoprecipitation, pulldown assay, siRNA/shRNA knockdown, immunofluorescence, cellular fractionation The Journal of biological chemistry High 17848569
2009 APPL2 dimerizes with APPL1 and acts as a negative regulator of adiponectin signaling in muscle cells: APPL2 overexpression inhibits APPL1-AdipoR1 interaction and suppresses downstream glucose uptake and fatty acid oxidation; adiponectin and metformin induce APPL1-APPL2 dissociation. Co-immunoprecipitation, RNAi, glucose uptake assay, fatty acid oxidation assay in C2C12 myotubes The Journal of biological chemistry High 19661063
2011 APPL1 recruits the inositol 5-phosphatases OCRL and Inpp5B to nascent phagosomes via active Rab5; knockdown of APPL1 or inhibition of Rab5 impairs OCRL/Inpp5B association with phagosomes and prolongs PI(4,5)P2 and actin on phagosome membranes, thereby affecting Akt signaling. siRNA knockdown, live imaging, co-immunoprecipitation, phosphoinositide detection Molecular biology of the cell High 22072788
2010 APPL1 scaffolds the TAK1-MKK3-p38 MAPK cascade in response to adiponectin: TAK1 and MKK3 bind to different regions of APPL1, and APPL1 overexpression or suppression selectively enhances or reduces adiponectin-stimulated p38 MAPK activation but not TNFα-stimulated p38 MAPK activation. In vitro affinity binding, co-immunoprecipitation, overexpression/siRNA in C2C12 cells American journal of physiology. Endocrinology and metabolism High 20978232
2014 APPL1 forms a complex with IRS1/2 under basal conditions; upon insulin or adiponectin stimulation, this complex is recruited to the insulin receptor in a manner dependent on APPL1 phosphorylation. APPL1 deletion in mice leads to systemic insulin resistance and a selective reduction in insulin-stimulated IRS1/2 (but not IR) tyrosine phosphorylation. Co-immunoprecipitation, APPL1 knockout mice, phosphorylation-dependent interaction assays Cell reports High 24813896
2009 APPL endosomes represent a distinct population of Rab5-positive sorting endosomes capable of sorting cargo for recycling or degradation, with long lifetimes; mathematical modeling of kinetic data rules out maturation of APPL vesicles into EEA1 endosomes as the primary mechanism, indicating APPL1 endosomes are a separate early endosomal compartment. Ultrastructural morphology analysis, kinetic cargo transport assays, mathematical modeling, live imaging The Journal of cell biology High 26459602
2012 APPL1 potentiates insulin secretion in pancreatic β cells by enhancing Akt-dependent expression of SNARE proteins (syntaxin-1, SNAP25, VAMP2); APPL1 knockout mice show impaired glucose-stimulated insulin secretion and reduced SNARE expression, which is rescued by constitutively active Akt. APPL1 knockout mice, transgenic overexpression, adenoviral rescue, exocytosis measurement, western blotting Proceedings of the National Academy of Sciences High 22566644
2009 APPL1 and APPL2 are novel activators of β-catenin/TCF-mediated transcription; both directly interact with the transcriptional repressor Reptin via the APPL1 PH domain, and are present in endogenous complexes containing Reptin, β-catenin, HDAC1, and HDAC2. APPL overexpression relieves Reptin-dependent repression by reducing HDAC association with Reptin. Reporter assay, co-immunoprecipitation, siRNA, chromatin immunoprecipitation The Journal of biological chemistry High 19433865
2009 APPL1 interacts with the NuRD co-repressor complex via HDAC2 (the key NuRD subunit for this association); HDAC1 levels regulate APPL1-NuRD interactions and modulate the nucleocytoplasmic distribution of APPL1, with HDAC1 silencing promoting nuclear localization of APPL1. APPL1 also has a NuRD-independent interaction with HDAC1 and affects p21WAF1/CIP1 expression. Co-immunoprecipitation, siRNA, overexpression, nuclear fractionation The Biochemical journal High 19686092
2011 APPL1 is required for basal NF-κB activity but not TNFα-stimulated NF-κB: APPL1 directly interacts with TRAF2 and synergizes with it to activate NF-κB upstream of the IKK complex. APPL1 increases NIK levels by reducing its association with the degradative TRAF2-TRAF3-cIAP1 complex, thereby triggering p65 nuclear translocation. Co-immunoprecipitation, siRNA/overexpression, gene expression profiling, luciferase reporter assay Journal of cell science High 22685329
2011 APPL1 regulates adiponectin-induced LKB1 cytosolic localization through a PP2A-PKCζ signaling pathway: adiponectin promotes APPL1 interaction with PP2A and PKCζ, leading to PP2A activation, PKCζ dephosphorylation/inactivation, LKB1 dephosphorylation at Ser307, and LKB1 cytosolic translocation to activate AMPK. Co-immunoprecipitation, kinase/phosphatase activity assays, subcellular fractionation, siRNA in C2C12 myotubes Molecular endocrinology High 21835890
2013 TRAF6 is an E3 ubiquitin ligase for APPL1; insulin induces Lys63-linked ubiquitination of APPL1 at Lys160 within the BAR domain. This ubiquitination is required for membrane localization of APPL1 and subsequent membrane recruitment and activation of Akt. A K160R mutant abolishes ubiquitination and membrane targeting, abrogating hepatic insulin sensitization. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, adenoviral gene delivery in obese mice The Biochemical journal High 23909487
2012 APPL1 in postsynaptic densities associates with the NMDAR complex through binding to PSD95 at its C-terminal PDZ-binding motif; synaptic NMDAR activity increases APPL1-PI3K/Akt complex formation and promotes neuroprotective Akt activation. Disrupting the APPL1-PSD95 interaction blocks synaptic NMDAR-dependent PI3K/Akt activation and neuroprotection. Co-immunoprecipitation, peptide competition, lentiviral knockdown, subcellular fractionation, cell survival assay The Journal of neuroscience High 22933778
2011 APPL1 localizes to dendritic spines and synapses, and regulates spine and synapse formation in hippocampal neurons. APPL1 knockdown reduces spine/synapse number; APPL1 increases active Akt in spines. The PTB domain (which binds Akt) is required, and APPL1 effects are dependent on Akt and downstream p21-activated kinase (PAK). siRNA knockdown, rescue with siRNA-resistant APPL1, dominant negative Akt, confocal imaging, surface AMPAR quantification Molecular and cellular neurosciences High 21236345
2012 APPL1 impairs cell migration by hindering adhesion turnover at the leading edge through inhibition of Akt activity at the cell edge and within adhesions; APPL1 decreases Src-dependent tyrosine phosphorylation of Akt, which is critical for Akt-mediated migration. siRNA knockdown, live-cell migration assay, TIRF microscopy for adhesion dynamics, Akt activity measurement Molecular biology of the cell High 22379109
2010 APPL1 proteins form homooligomers and heterooligomers via their BAR domains (necessary and sufficient for APPL-APPL interactions); all three domains (BAR, PH, PTB) target to cell membranes and bind phosphoinositides; full-length APPL-YFP recruits endogenous RAB5 to enlarged APPL-associated membrane structures. Co-immunoprecipitation, yeast two-hybrid, live cell imaging, phosphoinositide binding assay, FRET Traffic Medium 18034774
2010 APPL1 directly interacts with FRET-confirmed homotypic (APPL1-APPL1) and heterotypic (APPL1-APPL2) BAR domain-mediated contacts on curved cell membranes in vivo. FRET microscopy (sensitized emission, acceptor photobleaching, sequential photobleaching) PloS one Medium 20814572
2008 APPL1 interacts with OCRL (inositol 5-phosphatase mutated in Lowe syndrome); all known patient missense mutations in the ASH-RhoGAP domain of OCRL abolish APPL1 binding, and APPL1 and Rab5 independently recruit OCRL to endosomes. Co-immunoprecipitation, disease mutant analysis, endosome enlargement assay with constitutively active Rab5 Biochemical and biophysical research communications Medium 18307981
2010 APPL1 is required for efficient Akt activation by HGF (but not EGF or insulin) in murine embryonic fibroblasts; Appl1/Appl2 double knockdown further reduces HGF-induced Akt and impairs HGF-induced cell survival and migration. Appl1 knockout mouse, siRNA, cell survival and migration assays, growth factor stimulation The Journal of biological chemistry Medium 20040596
2015 APPL1 mediates βCTF (β-cleaved C-terminal fragment of APP)-induced Rab5 overactivation in Alzheimer's disease and Down syndrome: βCTF recruits APPL1 to Rab5 endosomes where it stabilizes GTP-bound Rab5, leading to accelerated endocytosis, endosome swelling, and impaired axonal transport of Rab5 endosomes. APPL1 knockdown corrects these endosomal anomalies in Down syndrome fibroblasts. Co-immunoprecipitation, siRNA knockdown, live imaging, endosome morphometry, axonal transport assay Molecular psychiatry High 26194181
2017 APPL1 is required for rapid recycling of LHR (luteinizing hormone receptor) from very early endosomes (VEEs) and for endosomal cAMP signaling; LHR recycling is driven by Gαs/cAMP signaling from the VEE and PKA-dependent phosphorylation of APPL1 at serine 410. siRNA knockdown, FRET-based cAMP biosensor, receptor recycling assay, phosphorylation mapping Cell reports High 29212031
2019 APPL1-positive endosomes in hippocampal axons exhibit predominantly retrograde motility; APPL1 endosomes transport TrkB and mediate retrograde axonal transport of Akt1. FRET analysis confirmed that APPL1 and Akt1 interact in an endocytosis-dependent manner. Live-cell imaging of primary mouse hippocampal neurons, FRET analysis, endosome tracking Scientific reports High 30792402
2019 Dynamin-1 (Dyn1), upregulated by gain-of-function mutant p53, recruits and stabilizes APPL1 on peripheral endosomes; these APPL1 endosomes modulate Akt signaling and activate Dyn1 in a positive feedback loop that promotes rapid recycling of EGFR and β1 integrins, focal adhesion turnover, and cell migration. siRNA knockdown, live imaging quantification of peripheral endosomes, integrin recycling assay, focal adhesion dynamics The Journal of cell biology High 31043431
2012 APPL1 is required for TLR3/4-dependent IRF3 activation; TBK1 and IKKε are recruited to APPL1 endosomes in LPS-stimulated macrophages. APPL1 undergoes proteasome-mediated degradation through ERK1/2 to terminate signaling, and this degradation is blocked when endosomal signaling is inhibited. siRNA knockdown, co-immunoprecipitation, proteasome inhibitors, chloroquine/dynasore treatment, IRF3 target gene expression Journal of immunology High 25780039
2016 APPL1 and APPL2 are required for TGFβ-induced nuclear translocation of the TGFβ type I receptor intracellular domain (TβRI-ICD) and for cancer cell invasiveness; APPL proteins associate with TβRI in a TRAF6-dependent manner. siRNA knockdown, co-immunoprecipitation, nuclear fractionation, invasion assay Oncotarget Medium 26583432
2012 APPL1 deficiency in β cells impairs glucose-stimulated insulin secretion by reducing mitochondrial function (oxygen consumption rate, ATP production, mitochondrial membrane potential) and expression of mitochondrial biogenesis genes. APPL1 knockout mice, hyperglycemic clamp, siRNA/overexpression in INS-1 cells, mitochondrial function assays Diabetologia High 23793716
2012 APPL1 phosphorylation at Ser430 by PKCα mediates ER stress-induced insulin resistance in hepatocytes: ER stress or PKCα activation increases APPL1 Ser430 phosphorylation; phosphomimetic APPL1(S430D) impairs Akt Thr308 phosphorylation, whereas APPL1(S430A) does not. Site-directed mutagenesis, siRNA, kinase assay, western blotting in mouse hepatocytes The Journal of biological chemistry High 22685300
2015 Two APPL1 loss-of-function mutations (p.Leu552* and p.Asp94Asn) in familial diabetes: Leu552* abolishes protein expression, while Asp94Asn significantly reduces APPL1-enhanced insulin-stimulated AKT2 and GSK3β phosphorylation, confirming that APPL1 enhances insulin-induced AKT2 activation in a physiologically relevant manner. Whole-exome sequencing, transfection in HepG2 cells, AKT2/GSK3β phosphorylation assay American journal of human genetics High 26073777
2011 Annexin A2 interacts with both APPL1 and APPL2 and co-fractionates with APPL endosomes; silencing Annexin A2 causes solubilization of APPL2 from endosomes, indicating it plays an important role in membrane recruitment of APPL proteins acting in parallel to Rab5. Co-immunoprecipitation, membrane fractionation, density gradients, siRNA knockdown Traffic Medium 21645192
2016 Serine 707 of APPL1 within its C-terminal PDZ-binding motif is a critical phosphorylation site for binding to the PDZ2 domain of PSD95 and for activation of the Akt signaling pathway during synaptic NMDAR activity. Co-immunoprecipitation, mutagenesis, western blotting in rat cortical neurons Neuroscience bulletin Medium 27300007
2021 APPL1 is required for early endosome-dependent mitophagy in macrophages: upon NLRP3 agonist stimulation, APPL1 translocates from early endosomes to mitochondria where it interacts with Rab5 to facilitate endosomal-mediated mitophagy, restricting NLRP3 inflammasome overactivation. APPL1-deficient macrophages accumulate damaged mitochondria producing ROS and oxidized mtDNA. APPL1 knockout mice (hematopoietic-specific), co-immunoprecipitation, mitophagy assay, NLRP3 inflammasome activation assay, live imaging Nature communications High 34789781
2011 APPL1 counteracts obesity-induced vascular insulin resistance by modulating the balance between Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in endothelium: APPL1 competes with TRB3 to potentiate Akt activation, and alters Raf-1 phosphorylation to suppress ERK1/2 signaling. APPL1 KO mice show shifted insulin response from vasodilation to vasoconstriction. APPL1 KO and transgenic mice, vascular reactivity assay, co-immunoprecipitation, endothelial cell signaling analysis Diabetes High 21926268
2004 APPL1 coimmunoprecipitates with FSH receptor (FSHR) in HEK 293 cells; FSHR co-immunoprecipitates with Akt; FSH treatment induces FOXO1a phosphorylation linking FSHR-APPL1 interaction to the PI3K/Akt pathway. Yeast two-hybrid, co-immunoprecipitation, FSH stimulation assay Biology of reproduction Medium 15070827
2011 APPL1 links FSHR to inositol 1,4,5-trisphosphate production and intracellular Ca2+ mobilization: mutation of FSHR-K376A abolishes APPL1 association without affecting FSH binding or cAMP production, but curtails IP3 production and Ca2+ mobilization from intracellular stores. Alanine scanning mutagenesis, co-immunoprecipitation, IP3 assay, Ca2+ imaging Endocrinology High 21285318
2003 APPL1 suppresses androgen receptor (AR) transactivation in a dose-dependent manner dependent on the PI3K/Akt pathway; APPL1 enhances IGF-1-mediated Akt activation; co-immunoprecipitation and GST pulldown show APPL1, Akt, and AR may exist in a complex with Akt bridging APPL1-AR association. Reporter gene assay, Northern blot, co-immunoprecipitation, GST pulldown, dominant negative constructs The Journal of biological chemistry Medium 12621049
2020 Membrane progesterone receptor β (mPRβ) signals through clathrin-dependent endocytosis into signaling endosomes where it transiently interacts with APPL1 and Akt2; APPL1 is required for mPRβ-mediated induction of Xenopus oocyte meiosis downstream of endocytosis. Xenopus oocyte meiosis assay, siRNA/morpholino knockdown, co-immunoprecipitation, endocytosis inhibition PLoS biology High 33137110
2016 APPL1 directly binds to both leptin receptor and STAT3; leptin stimulation enhances this interaction in a time-dependent manner and increases APPL1 phosphorylation; APPL1 overexpression or knockdown promotes or attenuates leptin-induced STAT3, ERK1/2, and Akt phosphorylation and cancer cell proliferation/migration. Co-immunoprecipitation, siRNA knockdown, overexpression, migration/proliferation assays PloS one Medium 27820851
2014 APPL1 and APPL2 interact with ATM after irradiation and are required for DNA double-strand break repair and ATM hyperphosphorylation; APPL knockdown reduces radiation survival in pancreatic carcinoma cells, and double targeting of APPL and ATM causes additive radiosensitization, suggesting APPL acts upstream of or directly on ATM. Co-immunoprecipitation, siRNA knockdown, clonogenic survival assay, γH2AX DSB repair assay Cell death & disease Medium 24763056
2016 APPL1 deficiency in β cells potentiates cytokine-induced NFκB activation (IκBα and p65 phosphorylation), leading to increased apoptotic and proinflammatory gene expression including iNOS; pharmacological NFκB or iNOS inhibition largely abrogates the detrimental effects of APPL1 deficiency. APPL1 KO mice, AAV overexpression, streptozotocin diabetes model, siRNA, phosphorylation assay Diabetologia High 28011992
2010 Cdo (a promyogenic cell surface protein) forms a complex with APPL1 and Boc in differentiating myoblasts; both Cdo and APPL1 are required for efficient Akt activation during myoblast differentiation, and constitutively active Akt rescues Cdo-depleted cell differentiation defects. Co-immunoprecipitation, siRNA knockdown, differentiation assay, constitutively active Akt rescue Molecular biology of the cell Medium 20484574

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nature cell biology 551 16622416
2004 APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Cell 458 15016378
2009 A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes. Cell 285 19303853
2007 Adiponectin-induced endothelial nitric oxide synthase activation and nitric oxide production are mediated by APPL1 in endothelial cells. Diabetes 279 17287464
2008 The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell 270 18455989
2008 APPL1: role in adiponectin signaling and beyond. American journal of physiology. Endocrinology and metabolism 234 18854421
1992 Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron 219 1389179
2009 Adiponectin activates AMP-activated protein kinase in muscle cells via APPL1/LKB1-dependent and phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathways. The Journal of biological chemistry 178 19520843
1999 Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2. Oncogene 172 10490823
2015 Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease. Molecular psychiatry 168 26194181
1999 Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport. Current biology : CB 165 10322116
2008 Adiponectin blocks interleukin-18-mediated endothelial cell death via APPL1-dependent AMP-activated protein kinase (AMPK) activation and IKK/NF-kappaB/PTEN suppression. The Journal of biological chemistry 130 18632660
2006 APPL1 associates with TrkA and GIPC1 and is required for nerve growth factor-mediated signal transduction. Molecular and cellular biology 122 17000777
1990 Identification, secretion, and neural expression of APPL, a Drosophila protein similar to human amyloid protein precursor. The Journal of neuroscience : the official journal of the Society for Neuroscience 120 2125311
2006 GIPC is recruited by APPL to peripheral TrkA endosomes and regulates TrkA trafficking and signaling. Molecular and cellular biology 117 17015470
2009 Yin-Yang regulation of adiponectin signaling by APPL isoforms in muscle cells. The Journal of biological chemistry 116 19661063
2011 Recruitment of OCRL and Inpp5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling. Molecular biology of the cell 115 22072788
2007 Structure of the APPL1 BAR-PH domain and characterization of its interaction with Rab5. The EMBO journal 114 17581628
2009 APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice. Cell metabolism 112 19416712
2015 Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus. American journal of human genetics 107 26073777
2007 The interaction of Akt with APPL1 is required for insulin-stimulated Glut4 translocation. The Journal of biological chemistry 105 17848569
2011 Adiponectin inhibits osteoclastogenesis and bone resorption via APPL1-mediated suppression of Akt1. The Journal of biological chemistry 104 21300805
2014 APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell reports 102 24813896
2002 The neurodegeneration mutant löchrig interferes with cholesterol homeostasis and Appl processing. The EMBO journal 98 12456644
2004 Human follicle-stimulating hormone (FSH) receptor interacts with the adaptor protein APPL1 in HEK 293 cells: potential involvement of the PI3K pathway in FSH signaling. Biology of reproduction 89 15070827
2011 Adiponectin-AdipoR1/2-APPL1 signaling axis suppresses human foam cell formation: differential ability of AdipoR1 and AdipoR2 to regulate inflammatory cytokine responses. Atherosclerosis 78 22227293
2006 APPL1, APPL2, Akt2 and FOXO1a interact with FSHR in a potential signaling complex. Molecular and cellular endocrinology 78 17030088
2018 Adiponectin attenuates neuronal apoptosis induced by hypoxia-ischemia via the activation of AdipoR1/APPL1/LKB1/AMPK pathway in neonatal rats. Neuropharmacology 76 29486166
2015 APPL endosomes are not obligatory endocytic intermediates but act as stable cargo-sorting compartments. The Journal of cell biology 75 26459602
2017 Integration of GPCR Signaling and Sorting from Very Early Endosomes via Opposing APPL1 Mechanisms. Cell reports 72 29212031
2010 APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway. American journal of physiology. Endocrinology and metabolism 71 20978232
2011 Globular adiponectin, acting via AdipoR1/APPL1, protects H9c2 cells from hypoxia/reoxygenation-induced apoptosis. PloS one 70 21552570
2011 The adapter protein APPL1 links FSH receptor to inositol 1,4,5-trisphosphate production and is implicated in intracellular Ca(2+) mobilization. Endocrinology 69 21285318
2012 APPL1 potentiates insulin secretion in pancreatic β cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice. Proceedings of the National Academy of Sciences of the United States of America 68 22566644
2021 The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages. Nature communications 65 34789781
2012 Endurance exercise training increases APPL1 expression and improves insulin signaling in the hepatic tissue of diet-induced obese mice, independently of weight loss. Journal of cellular physiology 60 21938726
2011 APPL1 mediates adiponectin-induced LKB1 cytosolic localization through the PP2A-PKCzeta signaling pathway. Molecular endocrinology (Baltimore, Md.) 58 21835890
2010 Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1. Proceedings of the National Academy of Sciences of the United States of America 57 20133602
2011 APPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice. Diabetes 56 21926268
2007 Crystal structures of the BAR-PH and PTB domains of human APPL1. Structure (London, England : 1993) 55 17502098
2003 APPL suppresses androgen receptor transactivation via potentiating Akt activity. The Journal of biological chemistry 55 12621049
2009 Endosomal adaptor proteins APPL1 and APPL2 are novel activators of beta-catenin/TCF-mediated transcription. The Journal of biological chemistry 54 19433865
2010 Rab5a overexpression promoting ovarian cancer cell proliferation may be associated with APPL1-related epidermal growth factor signaling pathway. Cancer science 51 20412119
2017 APPL1 is a multifunctional endosomal signaling adaptor protein. Biochemical Society transactions 50 28620038
2010 Cdo interacts with APPL1 and activates Akt in myoblast differentiation. Molecular biology of the cell 50 20484574
2015 Adiponectin enhances osteogenic differentiation in human adipose-derived stem cells by activating the APPL1-AMPK signaling pathway. Biochemical and biophysical research communications 49 25892517
2008 All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding. Biochemical and biophysical research communications 49 18307981
1996 APPL, the Drosophila member of the APP-family, exhibits differential trafficking and processing in CNS neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 8764652
2011 An APPL1/Akt signaling complex regulates dendritic spine and synapse formation in hippocampal neurons. Molecular and cellular neurosciences 47 21236345
2012 Adaptor protein APPL1 couples synaptic NMDA receptor with neuronal prosurvival phosphatidylinositol 3-kinase/Akt pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 46 22933778
2020 Adiponectin treatment improves insulin resistance in mice by regulating the expression of the mitochondrial-derived peptide MOTS-c and its response to exercise via APPL1-SIRT1-PGC-1α. Diabetologia 45 32880686
2009 Appl1 is dispensable for mouse development, and loss of Appl1 has growth factor-selective effects on Akt signaling in murine embryonic fibroblasts. The Journal of biological chemistry 45 20040596
2007 Membrane targeting by APPL1 and APPL2: dynamic scaffolds that oligomerize and bind phosphoinositides. Traffic (Copenhagen, Denmark) 45 18034774
2017 Intranasal administration of recombinant Netrin-1 attenuates neuronal apoptosis by activating DCC/APPL-1/AKT signaling pathway after subarachnoid hemorrhage in rats. Neuropharmacology 44 28347836
2014 Adiponectin mediated APPL1-AMPK signaling induces cell migration, MMP activation, and collagen remodeling in cardiac fibroblasts. Journal of cellular biochemistry 40 24255018
2011 The adaptor protein APPL1 increases glycogen accumulation in rat skeletal muscle through activation of the PI3-kinase signalling pathway. The Journal of endocrinology 39 21543456
2022 Adiponectin Ameliorates GMH-Induced Brain Injury by Regulating Microglia M1/M2 Polarization Via AdipoR1/APPL1/AMPK/PPARγ Signaling Pathway in Neonatal Rats. Frontiers in immunology 37 35720361
2014 AdipoR1/APPL1 potentiates the protective effects of globular adiponectin on angiotensin II-induced cardiac hypertrophy and fibrosis in neonatal rat atrial myocytes and fibroblasts. PloS one 37 25099270
2012 Exercise training performed simultaneously to a high-fat diet reduces the degree of insulin resistance and improves adipoR1-2/APPL1 protein levels in mice. Lipids in health and disease 37 23046739
2018 A collagen domain-derived short adiponectin peptide activates APPL1 and AMPK signaling pathways and improves glucose and fatty acid metabolisms. The Journal of biological chemistry 36 29991592
2011 Increased abundance of the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL1) in patients with obesity and type 2 diabetes: evidence for altered adiponectin signalling. Diabetologia 36 21562756
2010 Emerging roles for the FSH receptor adapter protein APPL1 and overlap of a putative 14-3-3τ interaction domain with a canonical G-protein interaction site. Molecular and cellular endocrinology 36 20600589
2013 APPL1 transgenic mice are protected from high-fat diet-induced cardiac dysfunction. American journal of physiology. Endocrinology and metabolism 35 23921137
2013 A novel mechanism for vascular insulin resistance in normotensive young SHRs: hypoadiponectinemia and resultant APPL1 downregulation. Hypertension (Dallas, Tex. : 1979) 33 23478100
2012 The PDZ protein GIPC regulates trafficking of the LPA1 receptor from APPL signaling endosomes and attenuates the cell's response to LPA. PloS one 33 23145131
2012 APPL1 regulates basal NF-κB activity by stabilizing NIK. Journal of cell science 29 22685329
2019 Retrograde transport of Akt by a neuronal Rab5-APPL1 endosome. Scientific reports 28 30792402
2019 High molecular weight adiponectin reduces glucolipotoxicity-induced inflammation and improves lipid metabolism and insulin sensitivity via APPL1-AMPK-GLUT4 regulation in 3T3-L1 adipocytes. Atherosclerosis 28 31330381
2016 APPL1-Mediating Leptin Signaling Contributes to Proliferation and Migration of Cancer Cells. PloS one 27 27820851
2012 The endosomal adaptor protein APPL1 impairs the turnover of leading edge adhesions to regulate cell migration. Molecular biology of the cell 27 22379109
2009 Functional characterization of the interactions between endosomal adaptor protein APPL1 and the NuRD co-repressor complex. The Biochemical journal 26 19686092
2015 Exenatide Activates the APPL1-AMPK-PPARα Axis to Prevent Diabetic Cardiomyocyte Apoptosis. Journal of diabetes research 24 26759813
2013 SNX15 links clathrin endocytosis to the PtdIns3P early endosome independently of the APPL1 endosome. Journal of cell science 24 23986476
2019 Mutant p53 amplifies a dynamin-1/APPL1 endosome feedback loop that regulates recycling and migration. The Journal of cell biology 22 31043431
2018 Curcumin alleviates ischemia reperfusion-induced late kidney fibrosis through the APPL1/Akt signaling pathway. Journal of cellular physiology 22 29741772
2014 APPL proteins modulate DNA repair and radiation survival of pancreatic carcinoma cells by regulating ATM. Cell death & disease 22 24763056
2011 Biochemical characterization of APPL endosomes: the role of annexin A2 in APPL membrane recruitment. Traffic (Copenhagen, Denmark) 22 21645192
2015 ESCRT-0 marks an APPL1-independent transit route for EGFR between the cell surface and the EEA1-positive early endosome. Journal of cell science 21 25588841
2013 Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function. Diabetologia 21 23793716
2013 TRAF6-mediated ubiquitination of APPL1 enhances hepatic actions of insulin by promoting the membrane translocation of Akt. The Biochemical journal 21 23909487
2006 Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development. Cell death and differentiation 21 16628230
2016 APPL proteins promote TGFβ-induced nuclear transport of the TGFβ type I receptor intracellular domain. Oncotarget 20 26583432
2016 Serine 707 of APPL1 is Critical for the Synaptic NMDA Receptor-Mediated Akt Phosphorylation Signaling Pathway. Neuroscience bulletin 20 27300007
2011 Adaptor protein containing PH domain, PTB domain and leucine zipper (APPL1) regulates the protein level of EGFR by modulating its trafficking. Biochemical and biophysical research communications 20 22037462
2020 Membrane progesterone receptor induces meiosis in Xenopus oocytes through endocytosis into signaling endosomes and interaction with APPL1 and Akt2. PLoS biology 19 33137110
2016 Incretin treatment and atherosclerotic plaque stability: Role of adiponectin/APPL1 signaling pathway. Journal of diabetes and its complications 18 27771154
2015 A role for APPL1 in TLR3/4-dependent TBK1 and IKKε activation in macrophages. Journal of immunology (Baltimore, Md. : 1950) 18 25780039
2012 β amyloid protein precursor-like (Appl) is a Ras1/MAPK-regulated gene required for axonal targeting in Drosophila photoreceptor neurons. Journal of cell science 18 23178937
2021 Activation of AdipoR1 with rCTRP9 Preserves BBB Integrity through the APPL1/AMPK/Nrf2 Signaling Pathway in ICH Mice. Oxidative medicine and cellular longevity 17 34925690
2020 Excessive reactive oxygen species induce apoptosis via the APPL1-Nrf2/HO-1 antioxidant signalling pathway in trophoblasts with missed abortion. Life sciences 17 32407842
2020 Miro, a Rho GTPase genetically interacts with Alzheimer's disease-associated genes (Tau, Aβ and Appl) in Drosophila melanogaster. Biology open 17 32747449
2016 APPL1 prevents pancreatic beta cell death and inflammation by dampening NFκB activation in a mouse model of type 1 diabetes. Diabetologia 17 28011992
2013 Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease. PloS one 17 23977033
2010 APPL proteins FRET at the BAR: direct observation of APPL1 and APPL2 BAR domain-mediated interactions on cell membranes using FRET microscopy. PloS one 17 20814572
2016 APPL1-mediated activation of STAT3 contributes to inhibitory effect of adiponectin on hepatic gluconeogenesis. Molecular and cellular endocrinology 16 27246173
2010 Appl1 is essential for the survival of Xenopus pancreas, duodenum, and stomach progenitor cells. Developmental dynamics : an official publication of the American Association of Anatomists 16 20568240
2021 Naringin Promotes Skeletal Muscle Fiber Remodeling by the AdipoR1-APPL1-AMPK Signaling Pathway. Journal of agricultural and food chemistry 15 34586803
2018 Resistance training recovers attenuated APPL1 expression and improves insulin-induced Akt signal activation in skeletal muscle of type 2 diabetic rats. American journal of physiology. Endocrinology and metabolism 15 29406784
2012 Phosphorylation of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif 1 (APPL1) at Ser430 mediates endoplasmic reticulum (ER) stress-induced insulin resistance in hepatocytes. The Journal of biological chemistry 15 22685300
2009 Loss of yata, a novel gene regulating the subcellular localization of APPL, induces deterioration of neural tissues and lifespan shortening. PloS one 15 19209226