Affinage

APPL1

DCC-interacting protein 13-alpha · UniProt Q9UKG1

Length
709 aa
Mass
79.7 kDa
Annotated
2026-06-09
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

APPL1 is a multidomain (BAR-PH-PTB) Rab5 effector that defines a distinct subpopulation of early endosomes and functions as a signaling scaffold coupling cell-surface receptors to intracellular kinase cascades and to the nucleus (PMID:15016378, PMID:17581628, PMID:17502098). Its crystallized N-terminal BAR-PH module forms a crescent-shaped dimer carrying two independent Rab-binding sites, with the PH domain directly engaging Rab5 and Rab21 switch regions, while all three domains can bind phosphoinositides and the BAR domain mediates APPL1/APPL2 homo- and hetero-oligomerization (PMID:17581628, PMID:17502098, PMID:18034774). APPL endosomes constitute long-lived tubulo-vesicular sorting compartments that route cargo for recycling or degradation and serve as intermediates in plasma membrane-to-nucleus signaling, from which APPL1 can translocate to the nucleus to interact with the NuRD complex via HDAC2 and with the β-catenin repressor Reptin to control chromatin and Wnt/TCF target genes (PMID:15016378, PMID:26459602, PMID:19433865, PMID:19686092). A dominant theme is potentiation of PI3K/Akt signaling: APPL1 binds inactive AKT2 and PI3K p110α through its PH/PTB domains, dictates Akt substrate specificity toward GSK-3β, blocks the Akt inhibitor TRB3, and facilitates IRS1/2 recruitment to the insulin receptor, thereby promoting insulin- and adiponectin-stimulated glucose uptake, GLUT4 translocation, suppression of hepatic gluconeogenesis, and glucose-stimulated insulin secretion in β cells (PMID:10490823, PMID:18455989, PMID:19416712, PMID:24813896, PMID:17848569, PMID:22566644). APPL1 also bridges adiponectin receptors AdipoR1/2 to AMPK activation by anchoring LKB1 in the cytosol and to a TAK1-MKK3-p38 MAPK scaffold, and these metabolic functions are tuned by post-translational modifications including TRAF6-mediated Lys63 ubiquitination at Lys160 (promoting membrane targeting) and inhibitory PKCα phosphorylation at Ser430 (PMID:16622416, PMID:17287464, PMID:19520843, PMID:20978232, PMID:23909487, PMID:22685300). Beyond metabolism, APPL1 acts at neuronal TrkA/TrkB and NMDAR/PSD95 complexes to drive PI3K/Akt-dependent neurite outgrowth, retrograde axonal transport, synapse formation, and synaptic plasticity, links TLR3/4 to TBK1/IKKε-dependent IRF3 activation, and restricts NLRP3 inflammasome activation by relocating to mitochondria to promote endosomal mitophagy (PMID:17000777, PMID:30792402, PMID:22933778, PMID:21236345, PMID:25780039, PMID:34789781). Loss-of-function mutations in APPL1 cause familial diabetes mellitus, consistent with its role in enhancing insulin-induced AKT2/GSK3β signaling (PMID:26073777).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1999 Medium

    Establishing that APPL1 physically links Akt to PI3K addressed how the kinase might be spatially organized in the cytoplasm, founding its role as a PI3K/Akt adaptor.

    Evidence Yeast two-hybrid, co-IP, and GST pulldown identifying APPL1 binding to inactive AKT2 and p110α via PH/PTB domains

    PMID:10490823

    Open questions at the time
    • Functional consequence of the tether not defined
    • No cellular localization context
  2. 2004 High

    Identifying APPL1/APPL2 as Rab5 effectors that translocate to the nucleus and bind NuRD established the endosome as an intermediate in membrane-to-nucleus signaling and connected APPL1 to chromatin regulation.

    Evidence Co-IP, subcellular fractionation, live imaging, siRNA, and MS in mammalian cells; plus FSHR co-IP linking APPL1 to a GPCR

    PMID:15016378 PMID:15070827

    Open questions at the time
    • NuRD subunit responsible not yet mapped
    • Nuclear target genes not identified
  3. 2006 High

    Demonstrating direct binding of APPL1 to adiponectin receptors and to TrkA/GIPC defined APPL1 as a receptor-proximal adaptor coupling distinct receptors to metabolic and neurotrophic signaling.

    Evidence Yeast two-hybrid, co-IP/MS, endosomal fractionation, and knockdown with glucose-uptake and neurite-outgrowth readouts

    PMID:16622416 PMID:17000777 PMID:17015470

    Open questions at the time
    • Precise mechanism of downstream kinase activation incompletely resolved
    • Receptor specificity determinants undefined
  4. 2007 High

    Crystal structures of BAR-PH and PTB domains and lipid/oligomerization assays explained how APPL1 dimerizes, binds Rab5/Rab21, and engages membranes, providing the structural basis for endosomal targeting.

    Evidence X-ray crystallography, mutagenesis, lipid-binding and yeast two-hybrid assays; AMPK/eNOS adiponectin signaling and AKT2/insulin functional studies

    PMID:17287464 PMID:17502098 PMID:17581628 PMID:17848569

    Open questions at the time
    • Structure of full-length protein with PTB not solved together
    • How modifications alter conformation unknown
  5. 2008 High

    In vivo zebrafish genetics showed APPL1 dictates Akt substrate specificity from endosomes, establishing that endosomal localization shapes signaling output rather than merely amplifying it.

    Evidence Morpholino knockdown, endosome fractionation, epistasis, and live imaging showing selective GSK-3β versus TSC2 phosphorylation

    PMID:18455989

    Open questions at the time
    • Molecular basis of substrate selection unresolved
    • Whether selectivity generalizes beyond fish
  6. 2009 High

    Multiple studies dissected how APPL1 potentiates metabolic Akt and AMPK signaling and how APPL2 antagonizes it, defining a balanced scaffold system for insulin/adiponectin action.

    Evidence Co-IP, competition assays, knockdown/overexpression, and in vivo hepatic rescue in db/db mice (TRB3 block, LKB1 anchoring, APPL2 sequestration); β-catenin/Reptin and PI3P-switch endosome studies

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

    Open questions at the time
    • Quantitative balance of APPL1/APPL2 in vivo not established
    • Tissue-specific roles incompletely mapped
  7. 2011 Medium

    Work expanded APPL1's scaffolding repertoire to NF-κB (TRAF2/NIK), NMDAR/PSD95 neuroprotection, synapse formation, phosphoinositide phosphatase recruitment, and FSHR Ca2+ signaling, showing one adaptor serving many receptor pathways.

    Evidence Co-IP, reporter assays, PSD fractionation, peptide disruption, phosphoinositide imaging, and mutagenesis across immune, neuronal, and reproductive systems

    PMID:21236345 PMID:21285318 PMID:21645192 PMID:21835890 PMID:22072788 PMID:22685329 PMID:22933778

    Open questions at the time
    • Most pathways shown in single labs
    • Endogenous stoichiometry across pathways unknown
  8. 2013 High

    Identifying TRAF6-mediated Lys63 ubiquitination at Lys160 and PKCα phosphorylation at Ser430, plus IRS1/2 recruitment and β-cell GSIS roles, revealed the regulatory PTM code controlling APPL1 membrane targeting and insulin sensitivity.

    Evidence Ubiquitination/phospho-site mutagenesis, E3-ligase identification, knockout mice, and in vivo rescue in obese/diabetic models

    PMID:22566644 PMID:22685300 PMID:23909487 PMID:24813896

    Open questions at the time
    • Crosstalk between distinct PTMs not resolved
    • Deubiquitinase/phosphatase counter-regulators unidentified
  9. 2015 High

    Loss-of-function APPL1 mutations causing familial diabetes and the βCTF-driven Rab5 overactivation in AD/Down syndrome established APPL1 as a disease-relevant node in metabolism and endosomal pathology.

    Evidence Whole-exome sequencing with functional AKT2/GSK3β assays; co-IP, live imaging, and rescue in DS fibroblasts and AD brain tissue; redefinition of APPL endosomes as long-lived sorting compartments

    PMID:26073777 PMID:26194181 PMID:26459602

    Open questions at the time
    • Penetrance and full mutation spectrum in diabetes unknown
    • Therapeutic targeting of APPL1-Rab5 in AD untested
  10. 2021 High

    Demonstrating APPL1 translocation to mitochondria to drive endosomal mitophagy and restrain NLRP3 inflammasome activation extended its role to innate immune homeostasis in vivo.

    Evidence Conditional knockout mice, co-IP with Rab5, live imaging, mitophagy and ROS assays, IL-1β secretion, and sepsis/obesity models; TLR-TBK1/IKKε IRF3 and TGFβ/T βRI-ICD invasion studies

    PMID:24763056 PMID:25780039 PMID:26583432 PMID:29212031 PMID:30792402 PMID:31043431 PMID:33137110 PMID:34789781

    Open questions at the time
    • Mechanism of APPL1 endosome-to-mitochondria relocation unclear
    • How APPL1 selects mitophagy versus signaling fates unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single adaptor integrates and prioritizes its many receptor and organelle interactions, and what governs its dynamic partitioning among endosomes, mitochondria, and the nucleus.
  • No unifying model of partitioning between compartments
  • Quantitative interactome stoichiometry undetermined
  • Structural basis of multi-receptor selectivity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005634 nucleus 4 GO:0005768 endosome 4 GO:0005829 cytosol 3 GO:0005886 plasma membrane 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2
Partners
ADIPOR1ADIPOR2AKT2APPL2OCRLRAB5TRAF6TRKA
Complex memberships
APPL1-APPL2 oligomerNuRD/HDAC2 complex

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 APPL1 (via its PTB domain) directly interacts with the cytoplasmic tails of adiponectin receptors AdipoR1 and AdipoR2 in mammalian cells; this interaction is stimulated by adiponectin. APPL1 overexpression increases, and knockdown reduces, adiponectin-stimulated lipid oxidation, glucose uptake, and GLUT4 membrane translocation. Adiponectin also stimulates APPL1-Rab5 interaction, contributing to GLUT4 translocation. APPL1 additionally mediates crosstalk between adiponectin and insulin signaling pathways. Yeast two-hybrid screen, co-immunoprecipitation, overexpression/knockdown with functional readouts (glucose uptake, GLUT4 translocation, lipid oxidation) Nature cell biology High 16622416
2004 APPL1 and APPL2 are Rab5 effectors residing on a subpopulation of early 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. Both APPL1 and APPL2 are essential for cell proliferation, and their function requires Rab5 binding. This identifies an endosomal compartment as an intermediate in plasma membrane-to-nucleus signaling. Co-immunoprecipitation, subcellular fractionation, live-cell imaging, siRNA knockdown with proliferation assays, mass spectrometry Cell High 15016378
2009 APPL endosomes represent an early endocytic intermediate derived from clathrin-coated vesicles and macropinosomes. Most APPL endosomes are precursors of PI3P-positive (EEA1) endosomes. PI3P acts as a molecular switch promoting this conversion: depletion of PI3P causes reversion of Rab5-positive endosomes to the APPL stage and results in enhanced growth factor signaling. Quantitative single-vesicle live-cell imaging, acute pharmacological and genetic manipulation of phosphoinositides (PI3P depletion), FRET Cell High 19303853
2008 In zebrafish, the endosomal protein Appl1 interacts with transmembrane receptors and Akt on endosomes; Appl1 regulates Akt activity and substrate specificity, selectively controlling GSK-3β phosphorylation but not TSC2 phosphorylation. Akt and GSK-3β, but not TSC2, dynamically associate with Appl1 endosomes upon growth factor stimulation. Appl1 function requires its endosomal localization, and it is selectively required for cell survival. Zebrafish genetics (morpholino knockdown), co-immunoprecipitation, endosome fractionation, live-cell imaging, epistasis analysis Cell High 18455989
1999 APPL1 (originally named APPL) was identified as a direct binding partner of AKT2 (the inactive form) and also binds PI3K catalytic subunit p110α. The interaction is mediated through APPL1's PH and PTB domains. APPL1 was proposed to tether inactive AKT2 to p110α in the cytoplasm. Yeast two-hybrid screen, co-immunoprecipitation, GST pulldown Oncogene Medium 10490823
2007 Crystal structures of the human APPL1 N-terminal BAR-PH domain reveal a crescent-shaped symmetrical dimer with a novel BAR domain architecture (two four-helical bundles) and PH domain at opposite ends. Two independent Rab-binding sites are located at the ends of the dimer; the PH domain directly interacts with Rab5 and Rab21 via β-strands, engaging both Rab5 switch regions. The BAR domain also contributes to Rab binding. X-ray crystallography, biochemical binding assays, site-directed mutagenesis The EMBO journal High 17502098 17581628
2007 Crystal structures of both the BAR-PH and PTB domains of human APPL1 were determined. The BAR domain dimer of APPL1 contains two four-helical bundles (distinct from other BAR domains). The PH domain locates at the opposite ends of the BAR domain dimer; BAR-PH interaction is confirmed by yeast two-hybrid. Lipid binding assays show that BAR, PH, and PTB domains can each bind phospholipids. X-ray crystallography, yeast two-hybrid (BAR-PH interaction), lipid-binding assay Structure High 17502098
2007 APPL1 interacts with adiponectin receptors (AdipoR1 and AdipoR2) in endothelial cells (confirmed by proteomic analysis of co-immunoprecipitation). Knockdown of APPL1 by RNAi significantly attenuates adiponectin-induced phosphorylation of AMPK at Thr172 and eNOS at Ser1177, and disrupts eNOS-HSP90 complex formation, reducing NO production. Adenoviral overexpression of constitutively active AMPK reverses these changes. Proteomics (co-IP/MS), RNAi knockdown, adenoviral overexpression, phospho-immunoblotting, NO measurement Diabetes High 17287464
2009 In muscle cells, APPL1 mediates adiponectin-induced AMPK activation through a major pathway: APPL1 directly interacts with adiponectin receptors and anchors LKB1 in the cytosol, promoting LKB1 cytosolic translocation and subsequent AMPK activation. A minor parallel pathway involves phospholipase C/Ca2+/CaMKK-dependent Ca2+ release from the ER. Co-immunoprecipitation, subcellular fractionation, overexpression/knockdown with signaling readouts, pharmacological inhibition The Journal of biological chemistry High 19520843
2009 APPL1 potentiates insulin-mediated Akt activation and suppression of hepatic gluconeogenesis by directly interacting with Akt and competitively blocking the association of Akt with its endogenous inhibitor TRB3, thereby promoting Akt translocation to the plasma membrane and endosomes. Hepatic overexpression of APPL1 in db/db diabetic mice attenuates hyperglycemia and insulin resistance. Co-immunoprecipitation, overexpression/knockdown, adenoviral hepatic overexpression in mice, competition binding assay Cell metabolism High 19416712
2006 APPL1 associates with TrkA and with the PDZ protein GIPC1 in sympathetic neurons and in endosomal fractions. The APPL1 PTB domain directly binds TrkA, and the PDZ domain of GIPC1 binds the C-terminal sequence of APPL1. APPL1, GIPC1, and phosphorylated TrkA co-enrich in endosomal fractions. Knockdown of APPL1 or GIPC1 suppresses NGF-dependent MEK, ERK, and Akt activation and neurite outgrowth. Co-immunoprecipitation, mass spectrometry (rat brain lysate pulldown), endosomal fractionation, siRNA knockdown, neurite outgrowth assay Molecular and cellular biology High 17000777
2006 Endogenous GIPC binds directly to the C-terminus of APPL1 on endosomes bearing TrkA. Upon NGF stimulation, GIPC and APPL1 translocate to TrkA-containing endocytic vesicles at cell process tips. GIPC's interaction with APPL1 is essential for GIPC recruitment to peripheral endosomes and for TrkA signaling (MAPK activation) and neurite outgrowth. GIPC is required for efficient endocytosis and trafficking of TrkA. Co-immunoprecipitation, live-cell imaging, siRNA knockdown, endosomal trafficking assays Molecular and cellular biology High 17015470
2009 APPL2 forms a dimer with APPL1 and acts as a negative regulator of adiponectin signaling in muscle cells. APPL2 interacts with both AdipoR1 and AdipoR2 and inhibits APPL1-AdipoR1 interaction. APPL2 overexpression inhibits adiponectin-stimulated glucose uptake and fatty acid oxidation; APPL2 knockdown enhances these responses. APPL2 also suppresses adiponectin/insulin signaling by sequestering APPL1. Adiponectin and metformin both induce APPL1-APPL2 dissociation. Co-immunoprecipitation, overexpression, RNAi knockdown, functional metabolic assays The Journal of biological chemistry High 19661063
2010 APPL1 mediates adiponectin-stimulated p38 MAPK activation by acting as a scaffolding protein that binds both TAK1 and MKK3 (at different regions of APPL1), facilitating the TAK1-MKK3-p38 MAPK cascade. Overexpression or knockdown of APPL1 enhances or suppresses, respectively, adiponectin-stimulated TAK1 and MKK3 activation. This scaffolding effect is selective for adiponectin signaling and not TNFα-stimulated p38 MAPK. In vitro affinity binding, co-immunoprecipitation, overexpression/knockdown with signaling readouts American journal of physiology. Endocrinology and metabolism Medium 20978232
2011 APPL1 recruits the inositol 5-phosphatases OCRL and Inpp5B to nascent phagosomes via active Rab5; these phosphatases deplete PtdIns(4,5)P2 from phagosome membranes. Knockdown of APPL1 or inhibition of Rab5 impairs phosphatase association with phagosomes and prolongs PtdIns(4,5)P2 and actin on phagosome membranes. APPL1 depletion paradoxically accentuates Akt activation by increasing available PtdIns(4,5)P2 for PI3K-dependent PtdIns(3,4,5)P3 generation. siRNA knockdown, phagocytosis assays, phosphoinositide imaging, fluorescence microscopy Molecular biology of the cell Medium 22072788
2008 APPL1 interacts with OCRL (inositol 5-phosphatase) via a specific short motif; all known disease-causing missense mutations in the ASH-RhoGAP domains of OCRL abolish APPL1 binding. APPL1 and Rab5 independently contribute to recruit OCRL to enlarged endosomes. Disruption of APPL1-OCRL interaction may contribute to Lowe syndrome and Dent disease pathology. Co-immunoprecipitation, mutagenesis, endosomal recruitment assays (Rab5Q79L enlarged endosomes) Biochemical and biophysical research communications Medium 18307981
2010 APPL1 binds OCRL via a short phenylalanine-and-histidine (F&H) motif; Ses1 and Ses2 (two endocytic proteins) share an overlapping OCRL-binding motif with APPL1, and their binding to OCRL is mutually exclusive with APPL1 binding. The same OCRL missense mutations that disrupt APPL1 binding also disrupt Ses1/2 binding. Co-immunoprecipitation, mutagenesis, endosomal localization studies Proceedings of the National Academy of Sciences of the United States of America Medium 20133602
2007 APPL1 interacts with Akt2 in primary rat adipocytes and skeletal muscle, forming a complex that dissociates upon insulin stimulation. APPL1 knockdown suppresses insulin-stimulated Akt phosphorylation, glucose uptake, and GLUT4 translocation. Expression of full-length APPL1 or its N-terminus suppresses insulin-stimulated glucose uptake and GLUT4 translocation. APPL1 partially co-localizes with GLUT4. Co-immunoprecipitation, pulldown, siRNA/shRNA knockdown, immunofluorescence, cellular fractionation, 2-deoxyglucose uptake assay The Journal of biological chemistry High 17848569
2003 APPL1 suppresses androgen receptor (AR) transactivation via potentiation of Akt activity; this effect is blocked by dominant-negative Akt, dominant-negative PI3K, or LY294002. APPL1 enhances IGF-1-mediated Akt activation. Co-immunoprecipitation and GST pulldown demonstrate APPL1, Akt, and AR may exist in a complex, with Akt serving as a bridge between APPL1 and AR. Reporter gene assay, Northern blot, co-immunoprecipitation, GST pulldown, dominant-negative overexpression The Journal of biological chemistry Medium 12621049
2009 APPL1 and APPL2 are novel activators of β-catenin/TCF-mediated transcription. Both APPL proteins interact directly with Reptin (a transcriptional repressor binding β-catenin and HDAC1), mapped to the PH domain of APPL1. APPL proteins are present in an endogenous complex with Reptin, β-catenin, HDAC1, and HDAC2. Overexpression of APPL proteins relieves Reptin-dependent transcriptional repression and reduces amounts of HDACs and β-catenin associated with Reptin. Co-immunoprecipitation, reporter assay, chromatin immunoprecipitation, domain-mapping (PH domain), siRNA knockdown The Journal of biological chemistry Medium 19433865
2009 In functional characterization of APPL1-NuRD interactions, HDAC2 was identified as the key NuRD subunit responsible for APPL1 association. APPL1 interacts with NuRD containing active HDAC2 but not HDAC1. Cellular HDAC1 levels regulate APPL1-NuRD binding, which modulates APPL1 nucleocytoplasmic distribution: increased APPL1-NuRD binding (upon HDAC1 silencing) promotes APPL1 nuclear localization. APPL1 also has a NuRD-independent interaction with HDAC1. Co-immunoprecipitation, siRNA knockdown, HDAC activity assays, subcellular fractionation, immunofluorescence The Biochemical journal Medium 19686092
2011 APPL1 directly interacts with TRAF2 in the NF-κB pathway and synergizes with TRAF2 to induce basal (but not TNFα-stimulated) NF-κB activation, functioning upstream of the IKK complex. Endosomal recruitment of APPL1 is required for its function in the NF-κB pathway. APPL1 overexpression markedly increases the level of NIK by reducing its association with the degradative TRAF2-TRAF3-cIAP1 complex, leading to nuclear translocation of p65. Co-immunoprecipitation, reporter assay, siRNA knockdown, overexpression, NF-κB pathway component analysis Journal of cell science Medium 22685329
2011 APPL1 is present in the postsynaptic density of rat cortical neurons and associates with the NMDAR complex through binding to PSD95 at its C-terminal PDZ-binding motif. NMDARs, APPL1, and the PI3K/Akt cascade form a complex in cortical neurons. Synaptic NMDAR activity increases this complex association and activates PI3K/Akt, protecting neurons from apoptosis. A peptide disrupting APPL1-PSD95 interaction, or APPL1 knockdown, blocks synaptic NMDAR-dependent PI3K/Akt activation and neuroprotection. Co-immunoprecipitation, postsynaptic density fractionation, peptide disruption, lentiviral knockdown, survival assay The Journal of neuroscience Medium 22933778
2011 APPL1 localizes to dendritic spines and synapses in hippocampal neurons. Knockdown of APPL1 decreases spine and synapse density, rescued by siRNA-resistant APPL1. The PTB domain of APPL1 (which binds Akt) is required for spine/synapse formation. APPL1 increases active Akt in spines/synapses, and effects on spine/synapse formation depend on Akt. APPL1 signaling also modulates spine/synapse formation through PAK. siRNA knockdown, rescue expression, immunofluorescence, surface AMPAR labeling, dominant-negative Akt, domain-deletion constructs Molecular and cellular neurosciences Medium 21236345
2010 APPL1 interacts with Cdo (a promyogenic cell surface protein) and Boc in differentiating myoblasts. Both Cdo and APPL1 are required for efficient Akt activation during myoblast differentiation. The promyogenic function of Cdo involves coordinated activation of p38MAPK via JLP/Bnip-2 scaffolds and Akt via APPL1. Co-immunoprecipitation, siRNA knockdown, rescue with constitutively active Akt, differentiation assays Molecular biology of the cell Medium 20484574
2015 APPL1 mediates Rab5 overactivation caused by elevated β-cleaved carboxy-terminal fragment of APP (βCTF) in Down syndrome and Alzheimer's disease. βCTF recruits APPL1 to Rab5 endosomes, where APPL1 stabilizes active GTP-Rab5, leading to accelerated endocytosis, endosome swelling, and impaired axonal transport of Rab5 endosomes. APPL1 knockdown in DS fibroblasts corrects these endosomal anomalies. Co-immunoprecipitation, siRNA knockdown, live-cell imaging, endocytosis assays, axonal transport assays in DS fibroblasts and AD brain tissue Molecular psychiatry High 26194181
2012 APPL1 promotes IRS1/2-insulin receptor (IR) interaction by forming a complex with IRS1/2 under basal conditions that is recruited to the IR upon insulin or adiponectin stimulation. This recruitment depends on insulin/adiponectin-stimulated APPL1 phosphorylation. Appl1 deletion in mice causes systemic insulin resistance and reduces insulin-stimulated IRS1/2 tyrosine phosphorylation without affecting IR tyrosine phosphorylation, placing APPL1 downstream of IR. Co-immunoprecipitation, appl1 knockout mice, insulin signaling assays, phosphorylation analysis Cell reports High 24813896
2012 APPL1 is required for glucose-stimulated insulin secretion (GSIS) in pancreatic β cells. APPL1 deficiency causes reduced expression of SNARE proteins (syntaxin-1, SNAP25, VAMP2) and decreased exocytotic events, associated with diminished insulin-stimulated Akt activation. Constitutively active Akt rescues the defective GSIS and SNARE protein expression in APPL1-deficient β cells. APPL1 knockout mice, transgenic mice, islet isolation, exocytosis assays, Akt activation assays, adenoviral rescue with constitutively active Akt Proceedings of the National Academy of Sciences of the United States of America High 22566644
2013 TRAF6 acts as an E3 ubiquitin ligase for APPL1, catalyzing insulin-induced Lys63-linked ubiquitination at Lys160 within the BAR domain. This ubiquitination promotes membrane localization of APPL1 and is required for Akt membrane recruitment/activation and suppression of gluconeogenesis. Replacement of Lys160 with arginine abolishes ubiquitination, membrane localization, and APPL1's insulin-sensitizing effects in obese mice. Ubiquitination assays, site-directed mutagenesis (K160R), co-immunoprecipitation (TRAF6 as E3 ligase), TRAF6 shRNA knockdown, adenoviral overexpression in mice The Biochemical journal High 23909487
2012 APPL1 phosphorylation at Ser430 is induced by PKCα (activated by ER stress or PMA) and is enhanced in livers of obese insulin-resistant mice. APPL1(S430D) but not APPL1(S430A) impairs the potentiating effect of APPL1 on insulin-stimulated Akt phosphorylation, identifying PKCα-mediated phosphorylation of APPL1 at Ser430 as a negative regulatory mechanism contributing to ER stress-induced insulin resistance. Phospho-specific antibody, site-directed mutagenesis (S430A/D), PKCα overexpression/knockdown, pharmacological activation, liver tissue analysis from obese mice The Journal of biological chemistry Medium 22685300
2011 APPL1 mediates adiponectin-induced LKB1 cytosolic translocation through a PP2A-PKCζ signaling pathway in muscle cells. Adiponectin promotes APPL1 interaction with PP2A and PKCζ, activating PP2A and causing dephosphorylation/inactivation of PKCζ. Inactivated PKCζ then dephosphorylates LKB1 at Ser307, leading to LKB1 cytosolic translocation and AMPK activation. Co-immunoprecipitation, phosphorylation analysis, pharmacological inhibition, overexpression/knockdown Molecular endocrinology Medium 21835890
2015 Loss-of-function mutations in APPL1 (p.Leu552* truncation abolishing protein expression, and p.Asp94Asn reducing APPL1 enhancement of insulin-stimulated AKT2 and GSK3β phosphorylation) cause familial diabetes mellitus. These mutations confirm that APPL1 enhances insulin-induced AKT2 activation and downstream signaling essential for insulin action. Whole-exome sequencing, transfection of mutant constructs in HepG2 cells, western blotting of AKT2 and GSK3β phosphorylation American journal of human genetics Medium 26073777
2012 APPL1 impairs cell migration by hindering adhesion turnover at the leading edge. The mechanism involves inhibition of Akt activity at the cell edge and within adhesions. APPL1 also significantly decreases Src-mediated tyrosine phosphorylation of Akt, which is critical for Akt-mediated migration. Overexpression/knockdown, live-cell imaging of adhesion dynamics, Akt activity assays, Src inhibition Molecular biology of the cell Medium 22379109
2017 APPL1 plays a role in rapid recycling of the luteinizing hormone receptor (LHR) from very early endosomes (VEEs) and enables endosomal cAMP signaling. LHR recycling is driven by receptor-mediated Gαs/cAMP signaling from the VEE, and PKA-dependent phosphorylation of APPL1 at serine 410 drives recycling. APPL1 phosphorylation regulates receptor/Gαs endosomal signaling in VEE microdomains. siRNA knockdown, live-cell imaging, FRET, overexpression of phospho-mutant APPL1 (S410A/D), cAMP biosensors Cell reports Medium 29212031
2016 APPL1 is required for TLR3/4-dependent TBK1 and IKKε activation in macrophages. APPL1 endosomes recruit TBK1 and IKKε upon LPS stimulation. APPL1 deficiency impairs IRF3 target gene expression in response to TLR3, TLR4, and H1N1 virus. APPL1 undergoes ERK1/2-dependent proteasome-mediated degradation to turn off signaling; this degradation is blocked by endosomal signaling inhibitors. siRNA knockdown, immunofluorescence colocalization, IRF3 activation assays, viral infection models, proteasome inhibition Journal of immunology Medium 25780039
2019 APPL1-positive endosomes in hippocampal axons display predominantly retrograde motility and mediate retrograde axonal transport of TrkB receptor and Akt1. FRET analysis shows that APPL1 and Akt1 interact in an endocytosis-dependent manner on these endosomes. The level of endosomal APPL1 correlates with faster retrograde movement. Live-cell imaging, FRET, endocytosis inhibition, endosomal fractionation in primary hippocampal neurons Scientific reports Medium 30792402
2015 APPL1 endosomes represent a distinct population of long-lived Rab5-positive sorting endosomes (tubulo-vesicular compartment) capable of sorting cargo for recycling or degradation, rather than being obligatory transient intermediates that mature into EEA1 endosomes. Mathematical modeling of cargo kinetics rules out maturation as the primary cargo transport mechanism. Quantitative live-cell imaging (ultrastructure, kinetics), mathematical modeling, electron microscopy The Journal of cell biology High 26459602
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, and this association promotes nuclear transport of TβRI-ICD and transcription of pro-invasive genes (MMP2, MMP9). Co-immunoprecipitation, siRNA knockdown, invasion assays, nuclear fractionation, immunohistochemistry in prostate cancer tissue Oncotarget Medium 26583432
2019 Dynamin-1 (Dyn1) is upregulated by gain-of-function mutant p53 and is required for the accumulation of APPL1 on a spatially localized subpopulation of perimeter endosomes. These perimeter APPL1 endosomes modulate Akt signaling and activate Dyn1 to create a positive feedback loop required for rapid recycling of EGFR and β1 integrins, focal adhesion turnover, and cell migration. Live-cell imaging, quantitative endosome tracking, siRNA knockdown, integrin recycling assays, Akt activity measurement The Journal of cell biology Medium 31043431
2014 APPL proteins modulate DNA repair and radiation survival of pancreatic carcinoma cells by regulating ATM. APPL1 knockdown diminishes radiogenic hyperphosphorylation of ATM and impairs DNA double-strand break repair. Activated ATM and APPL1 interact after irradiation, suggesting a direct role for APPL1 in ATM phosphorylation. siRNA knockdown, clonogenic survival assay, DNA DSB repair assays (γH2AX foci), co-immunoprecipitation after irradiation Cell death & disease Medium 24763056
2021 APPL1 restricts NLRP3 inflammasome activation through 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. APPL1 deletion impairs mitophagy, leading to accumulation of damaged mitochondria and ROS, triggering NLRP3 inflammasome hyperactivation. Hematopoietic APPL1-deficient mice show enhanced susceptibility to endotoxin sepsis and obesity-induced inflammation. Conditional knockout mice, co-immunoprecipitation, live-cell imaging, mitophagy assays, mitochondrial ROS measurement, IL-1β secretion assays Nature communications High 34789781
2004 APPL1 co-immunoprecipitates with the FSH receptor (FSHR) in HEK293 cells stably expressing FSHR, establishing APPL1 as a FSHR-interacting protein. FSH treatment activates FOXO1a phosphorylation and FSHR co-immunoprecipitates with Akt, providing a link between FSHR and PI3K/Akt signaling via APPL1. Yeast two-hybrid screen, co-immunoprecipitation, phosphorylation assays Biology of reproduction Medium 15070827
2011 The adapter protein APPL1 links the FSH receptor to inositol 1,4,5-trisphosphate (IP3) production and Ca2+ mobilization. Alanine substitution of FSHR-K376 in the first intracellular loop abolishes APPL1 association without affecting FSH binding or cAMP production. FSHR-K376A mutant shows reduced IP3 production and impaired Ca2+ mobilization from intracellular stores in response to FSH. Alanine-scanning mutagenesis, co-immunoprecipitation, IP3 production assay, intracellular Ca2+ measurement, FSH binding assay Endocrinology Medium 21285318
2020 Membrane progesterone receptor β (mPRβ) signaling in Xenopus oocyte meiosis requires APPL1 and Akt2. Progesterone induces clathrin-dependent endocytosis of mPRβ into signaling endosomes, where mPRβ transiently interacts with APPL1 and Akt2 to induce meiosis. Xenopus oocyte meiosis assay, clathrin inhibition, co-immunoprecipitation, siRNA knockdown PLoS biology Medium 33137110
2011 Annexin A2 was identified as a binding partner of both APPL1 and APPL2 on APPL endosomes. Annexin A2 co-fractionates and co-localizes with APPL endosomes. Silencing Annexin A2 causes solubilization of APPL2 from endosomes, indicating Annexin A2 contributes to APPL membrane recruitment in parallel to Rab5. Membrane fractionation, co-immunoprecipitation, siRNA knockdown, density gradient centrifugation, immunofluorescence Traffic Medium 21645192
2016 APPL1 knockdown specifically impairs PI3K-dependent forms of hippocampal synaptic plasticity (LTP and mGluR-LTD). APPL1 is required for activation of the PIP3 pathway in response to LTP induction, and this requirement is related to phosphoinositide binding by APPL1's PH domain. Membrane localization of PI3K bypasses the APPL1 requirement. PDK1 and Akt inhibitors do not affect LTP expression, indicating downstream PIP3 effectors other than PDK1/Akt mediate this function. siRNA knockdown in hippocampal slices, electrophysiology (LTP/LTD), PI3P/PIP3 biosensors, PI3K membrane-targeting constructs, pharmacological inhibitors Journal of cell science Medium 27257087
2007 Full-length APPL1 and APPL2 form homooligomers and heterooligomers via their BAR domains; the minimal BAR domain is necessary and sufficient for APPL-APPL interactions. All three domains (BAR, PH, PTB) can target to cell membranes independently. Full-length APPL proteins bind phosphoinositides in vitro; PH and PTB domains alone are sufficient for phosphoinositide binding. Co-immunoprecipitation, yeast two-hybrid, live-cell imaging (YFP fusion), in vitro phosphoinositide binding assay Traffic Medium 18034774

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 459 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 280 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 235 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 170 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
2011 Adiponectin inhibits osteoclastogenesis and bone resorption via APPL1-mediated suppression of Akt1. The Journal of biological chemistry 105 21300805
2007 The interaction of Akt with APPL1 is required for insulin-stimulated Glut4 translocation. The Journal of biological chemistry 105 17848569
2014 APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell reports 103 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
2021 The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages. Nature communications 71 34789781
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
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 58 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 57 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
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 47 22933778
2011 An APPL1/Akt signaling complex regulates dendritic spine and synapse formation in hippocampal neurons. Molecular and cellular neurosciences 47 21236345
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 41 24255018
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 39 35720361
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
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 37 29991592
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
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
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 29 31330381
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
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 25 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
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 22 25588841
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
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
2021 Activation of AdipoR1 with rCTRP9 Preserves BBB Integrity through the APPL1/AMPK/Nrf2 Signaling Pathway in ICH Mice. Oxidative medicine and cellular longevity 19 34925690
2020 Membrane progesterone receptor induces meiosis in Xenopus oocytes through endocytosis into signaling endosomes and interaction with APPL1 and Akt2. PLoS biology 19 33137110
2020 Miro, a Rho GTPase genetically interacts with Alzheimer's disease-associated genes (Tau, Aβ and Appl) in Drosophila melanogaster. Biology open 18 32747449
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
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
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
2016 APPL1 gates long-term potentiation through its plekstrin homology domain. Journal of cell science 15 27257087
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

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