APPL1

Summary

APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1, HGNC:24035) is a protein-coding gene on chromosome 3p14.3, encoding DCC-interacting protein 13-alpha (Q9UKG1). Multifunctional adapter protein that binds to various membrane receptors, nuclear factors and signaling proteins to regulate many processes, such as cell proliferation, immune response, endosomal trafficking and cell metabolism.

The protein encoded by this gene has been shown to be involved in the regulation of cell proliferation, and in the crosstalk between the adiponectin signalling and insulin signalling pathways. The encoded protein binds many other proteins, including RAB5A, DCC, AKT2, PIK3CA, adiponectin receptors, and proteins of the NuRD/MeCP1 complex. This protein is found associated with endosomal membranes, but can be released by EGF and translocated to the nucleus.

Source: NCBI Gene 26060 — RefSeq curated summary.

At a glance

• Gene–disease (curated): maturity-onset diabetes of the young type 14 (Strong, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 274 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 32
• MANE Select transcript: NM_012096

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24035
Approved symbol	APPL1
Name	adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Aliases	APPL
Ensembl gene	ENSG00000157500
Ensembl biotype	protein_coding
OMIM	604299
Entrez	26060

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay

ENST00000288266, ENST00000444459, ENST00000464446, ENST00000468342, ENST00000482800, ENST00000488530, ENST00000492501, ENST00000495803, ENST00000650354, ENST00000855520, ENST00000855521, ENST00000855522, ENST00000855523, ENST00000855524, ENST00000855525, ENST00000924302, ENST00000946518, ENST00000946519, ENST00000946520

RefSeq mRNA: 1 — MANE Select: NM_012096 NM_012096

CCDS: CCDS2882

Canonical transcript exons

ENST00000288266 — 22 exons

Exon	Start	End
ENSE00001032946	57268398	57268487
ENSE00001121992	57269541	57273471
ENSE00001277615	57227729	57227937
ENSE00003461140	57259028	57259080
ENSE00003465942	57256957	57257051
ENSE00003472631	57253682	57253738
ENSE00003516737	57259845	57260019
ENSE00003522948	57238045	57238116
ENSE00003560629	57240465	57240552
ENSE00003566230	57260117	57260153
ENSE00003577757	57235566	57235664
ENSE00003594957	57267742	57267792
ENSE00003599120	57237492	57237551
ENSE00003603225	57257246	57257428
ENSE00003634217	57252269	57252311
ENSE00003648000	57248193	57248351
ENSE00003656992	57249360	57249548
ENSE00003666816	57242856	57242914
ENSE00003674112	57246076	57246222
ENSE00003674290	57260628	57260774
ENSE00003688235	57247395	57247477
ENSE00003786983	57242101	57242142

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 95.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.1633 / max 264.2912, expressed in 1800 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36985	17.5758	1776
36987	6.6474	1668
36986	0.9401	595

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	95.58	gold quality
biceps brachii	UBERON:0001507	92.25	gold quality
germinal epithelium of ovary	UBERON:0001304	92.04	gold quality
adrenal tissue	UBERON:0018303	92.03	gold quality
body of pancreas	UBERON:0001150	91.66	gold quality
muscle of leg	UBERON:0001383	91.03	gold quality
vastus lateralis	UBERON:0001379	90.87	gold quality
penis	UBERON:0000989	90.66	gold quality
muscle organ	UBERON:0001630	90.66	gold quality
skeletal muscle organ	UBERON:0014892	90.66	gold quality
gastrocnemius	UBERON:0001388	90.58	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.43	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.84	gold quality
pancreas	UBERON:0001264	89.77	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.51	gold quality
skeletal muscle tissue	UBERON:0001134	89.49	gold quality
quadriceps femoris	UBERON:0001377	89.48	gold quality
colonic epithelium	UBERON:0000397	89.04	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.04	gold quality
esophagus squamous epithelium	UBERON:0006920	89.01	gold quality
islet of Langerhans	UBERON:0000006	88.97	gold quality
tendon	UBERON:0000043	88.92	gold quality
superficial temporal artery	UBERON:0001614	88.76	gold quality
muscle tissue	UBERON:0002385	88.00	gold quality
deltoid	UBERON:0001476	87.98	silver quality
nipple	UBERON:0002030	87.98	gold quality
corpus callosum	UBERON:0002336	87.98	gold quality
bone marrow cell	CL:0002092	87.87	gold quality
monocyte	CL:0000576	87.82	gold quality
urethra	UBERON:0000057	87.60	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, RELA

miRNA regulators (miRDB)

280 targeting APPL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-32-5P	99.98	75.21	1964

Literature-anchored findings (GeneRIF, showing 40)

• identification of a pathway directly linking the small GTPase Rab5, a key regulator of endocytosis, to signal transduction and mitogenesis via APPL1 and APPL2, two Rab5 effectors (PMID:15016378)
• APPL1 is a potential interactor with FSHR (PMID:15070827)
• APPL1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin. (PMID:16622416)
• APPL1 acts as a common downstream effector of Adiponectin receptors R1 and -R2, mediating adiponectin-evoked endothelial nitric oxide production and endothelium-dependent vasodilation. (PMID:17287464)
• The ability of APPL1 to interact with multiple signaling molecules and phospholipids supports an important role for this adaptor in cell signaling. (PMID:17502098)
• The crystal structures of human APPL1 N-terminal BAR-PH domain motif, is reported. (PMID:17581628)
• These data suggest that APPL1 plays an important role in insulin-stimulated Glut4 translocation in muscle and adipose tissues and that its N-terminal portion may be critical for APPL1 function. (PMID:17848569)
• The findings suggest a role for APPL1 and APPL2 protein as dynamic scaffolds that modulate RAB5-associated signaling endosomal membranes by their ability to undergo domain-mediated oligomerization, membrane targeting and phosphoinositide binding. (PMID:18034774)
• Thus, binding to APPL1 helps localize OCRL at specific cellular sites, and disruption of this interaction may play a role in disease. (PMID:18307981)
• Adiponectin blocks interleukin-18-mediated endothelial cell death via APPL1-dependent AMP-activated protein kinase (AMPK) activation and IKK/NF-kappaB/PTEN suppression. (PMID:18632660)
• APPL proteins exert their stimulatory effects on beta-catenin/TCF-dependent transcription by decreasing the activity of a Reptin-containing repressive complex (PMID:19433865)
• 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 (PMID:19520843)
• APPL1 overexpression affects the composition of the HDAC1-containing NuRD complex and the expression of HDAC1 target p21WAF1/CIP1 (PMID:19686092)
• Used mass spectrometry (MS) to identify 13 phosphorylated residues within APPL1. (PMID:20095645)
• Rab5a promoted proliferation of ovarian cancer cells, which may be associated with the APPL1-related epidermal growth factor signaling pathway. (PMID:20412119)
• The promyogenic function of Cdo involves a coordinated activation of p38MAPK and Akt via association with scaffold proteins, JLP and Bnip-2 for p38MAPK and APPL1 for Akt. (PMID:20484574)
• [REVIEW] Emerging roles for AppL1. APPL1 has been shown to interact with a variety of membrane receptors. Recent subcellular localizations of APPL1 place it in dynamic and varied venues in the cell: the cell membrane, the nucleus and the early endosomes (PMID:20600589)
• significant fluorescence resonance energy transfer between APPL minimal BAR domain FRET pairs (PMID:20814572)
• Studies indicate that APPL1 has been recently identified as an AdipoR1 and AdipoR2 binding protein. (PMID:20875820)
• Data indicate APPL1 functions as a scaffolding protein to facilitate adiponectin-stimulated p38 MAPK activation in myotubes. (PMID:20978232)
• The adapter protein APPL1 links FSH receptor to inositol 1,4,5-trisphosphate production and is implicated in intracellular Ca(2+) mobilization. (PMID:21285318)
• interactions between TRP1-GIPC and GIPC-APPL-AKT provide a potential link between melanogenesis and PI3 kinase signaling (PMID:21291857)
• Results show that APPL1 is recruited to aggresomes induced by proteasomal stress, and suggest that proteasome inhibitors in clinical use affect the localization, ubiquitination and solubility of APPL1. (PMID:21320486)
• APPL1 abundance is significantly higher in type 2 diabetic muscle; Improvements in hyperglycaemia and hypoadiponectinaemia are associated with reduced skeletal muscle APPL1, and increased plasma adiponectin levels and muscle AMPK phosphorylation. (PMID:21562756)
• Data suggest that although annexin A2 is not an exclusive marker of APPL1/2 endosomes, it has an important function in membrane recruitment of APPL proteins, acting in parallel to Rab5. (PMID:21645192)
• Treating C2C12 myotubes with adiponectin promoted APPL1 interaction with protein phosphatase 2A (PP2A) and protein kinase Czeta (PKCzeta), leading to the activation of PP2A and subsequent dephosphorylation and inactivation of PKCzeta. (PMID:21835890)
• APPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium. (PMID:21926268)
• These findings suggest that APPL1 is required for EGFR signaling by regulation of EGFR stabilities through inhibition of Rab5. (PMID:22037462)
• Genetic variation(s) in APPL1/2 may be associated with CAD risk in T2DM in Chinese population. (PMID:22340213)
• results demonstrate an important new function for APPL1 in regulating cell migration and adhesion turnover through a mechanism that depends on Src and Akt (PMID:22379109)
• APPL1 is a novel target in endoplasmic reticulum (ER) stress-induced insulin resistance and PKCalpha is the kinase mediating ER stress-induced phosphorylation of APPL1 at Ser(430). (PMID:22685300)
• APPL1 regulates basal NF-kappaB activity by modulating the stability of NIK, which affects the activation of p65. (PMID:22685329)
• analysis of APPL1 and APPL2 proteins and their interaction with Rab (PMID:23055524)
• neurons with APPL1-positive granules were restricted to the CA1 area and subiculum, areas associated with hippocampal vulnerability, suggesting a possible link between the perisomatic accumulation of APPL1 and Alzheimer’s disease. (PMID:23246927)
• Rab5a and APPL1 are overexpressed in breast cancer, and are positively correlated with the HER-2 expression. (PMID:23291133)
• It concludes that APPL1(PH) binding to BAR domain and Reptin is mutually exclusive which regulates the nucleocytoplasmic shuttling of Reptin. (PMID:23891720)
• TRAF6-mediated ubiquitination of APPL1 is a vital step for the hepatic actions of insulin through modulation of membrane trafficking and activity of Akt. (PMID:23909487)
• C-APPL1/A-APPL2 allele combination is associated with non-alcoholic fatty liver disease occurrence, with a more severe hepatic steatosis grade and with a reduced adiponectin cytoprotective effect on liver. (PMID:23977033)
• The activated EGF receptor enters distinct sub-populations of SNX15- and APPL1-labelled peripheral endocytic vesicles. (PMID:23986476)
• ATM is the central modulator of APPL-mediated effects on radiosensitivity and DNA repair. (PMID:24763056)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	appl1	ENSDARG00000060734
mus_musculus	Appl1	ENSMUSG00000040760
rattus_norvegicus	Appl1	ENSRNOG00000013574

Paralogs (28): ARAP2 (ENSG00000047365), ACAP1 (ENSG00000072818), SMAP2 (ENSG00000084070), ASAP3 (ENSG00000088280), ARFGAP1 (ENSG00000101199), ADAP1 (ENSG00000105963), AGFG2 (ENSG00000106351), GIT1 (ENSG00000108262), SMAP1 (ENSG00000112305), ACAP2 (ENSG00000114331), ARAP3 (ENSG00000120318), ACAP3 (ENSG00000131584), AGAP3 (ENSG00000133612), AGAP2 (ENSG00000135439), APPL2 (ENSG00000136044), GIT2 (ENSG00000139436), ARFGAP2 (ENSG00000149182), ASAP2 (ENSG00000151693), ASAP1 (ENSG00000153317), AGAP1 (ENSG00000157985), AGAP5 (ENSG00000172650), AGFG1 (ENSG00000173744), ADAP2 (ENSG00000184060), ARAP1 (ENSG00000186635), AGAP4 (ENSG00000188234), AGAP6 (ENSG00000204149), AGAP9 (ENSG00000204172), ARFGAP3 (ENSG00000242247)

Protein

Protein identifiers

DCC-interacting protein 13-alpha — Q9UKG1 (reviewed: Q9UKG1)

Alternative names: Adapter protein containing PH domain, PTB domain and leucine zipper motif 1

All UniProt accessions (3): Q9UKG1, C9JAB0, C9K0C4

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional adapter protein that binds to various membrane receptors, nuclear factors and signaling proteins to regulate many processes, such as cell proliferation, immune response, endosomal trafficking and cell metabolism. Regulates signaling pathway leading to cell proliferation through interaction with RAB5A and subunits of the NuRD/MeCP1 complex. Functions as a positive regulator of innate immune response via activation of AKT1 signaling pathway by forming a complex with APPL1 and PIK3R1. Inhibits Fc-gamma receptor-mediated phagocytosis through PI3K/Akt signaling in macrophages. Regulates TLR4 signaling in activated macrophages. Involved in trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner. Plays a role in cell metabolism by regulating adiponecting and insulin signaling pathways. Required for fibroblast migration through HGF cell signaling. Positive regulator of beta-catenin/TCF-dependent transcription through direct interaction with RUVBL2/reptin resulting in the relief of RUVBL2-mediated repression of beta-catenin/TCF target genes by modulating the interactions within the beta-catenin-reptin-HDAC complex.

Subunit / interactions. Homodimer. Binds RAB5A/Rab5 through an N-terminal domain. This interaction is essential for its recruitment to endosomal membranes as well as its role in cell proliferation. Binds DCC and the catalytic domain of the inactive form of AKT2 through its PID domain. Binds PIK3CA and subunits of the NuRD/MeCP1 complex. Interacts with OCRL and INPP5B. Interacts with NTRK2. Interacts with APPL2; interaction is independent of follicle stimulating hormone stimulation; interaction is decreased by adiponectin in a time-dependent manner. Forms a complex with APPL2 and RUVBL2. Forms a complex comprising APPL2, RUVBL2, CTNNB1, HDAC1 and HDAC2; interaction reduces interaction between CTNNB1, HDAC1, HDAC2 and RUVBL2 leading to the decrease of deacetylase activity of this complex; affects the recruitment of repressive complexes to the Wnt target genes. Interacts with ANXA2. Interacts with TGFBR1; interaction is TGF beta dependent; mediates trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner. Interacts with PRKCZ. Interacts with PIK3R1 and APPL2. Interacts with ADIPOR1; ADIPOQ enhances this interaction; inhibits adiponectin-stimulated binding of APPL2 to ADIPOR1.

Subcellular location. Early endosome membrane. Nucleus. Cytoplasm. Endosome. Cell projection. Ruffle. Cytoplasmic vesicle. Phagosome.

Tissue specificity. High levels in heart, ovary, pancreas and skeletal muscle.

Post-translational modifications. Phosphorylation at Ser-410 by PKA severely impairs binding to OCRL.

Disease relevance. Maturity-onset diabetes of the young 14 (MODY14) [MIM:616511] A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Overexpression of an N-terminal domain (residues 1-319) or a C-terminal region (residues 273-709) has a proapoptotic effect. The F&H motif, an approximately 12-13 amino-acid sequence centered around Phe and His residues, is essential for binding to OCRL and INPP5B.

RefSeq proteins (1): NP_036228* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR004148	BAR_dom	Domain
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR037929	DP13A_BAR	Domain
IPR047181	DP13A/B	Family
IPR047236	PH_DP13A/B	Domain
IPR047237	PTB_APPL	Domain

Pfam: PF00169, PF00640, PF16746

UniProt features (57 total): strand 16, helix 14, modified residue 5, sequence variant 4, region of interest 4, domain 3, compositionally biased region 3, turn 3, coiled-coil region 2, chain 1, short sequence motif 1, mutagenesis site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
2Q12	X-RAY DIFFRACTION	1.79
2EJ8	X-RAY DIFFRACTION	1.84
2Z0N	X-RAY DIFFRACTION	1.95
2ELA	X-RAY DIFFRACTION	2
2Q13	X-RAY DIFFRACTION	2.05
2Z0O	X-RAY DIFFRACTION	2.58
2ELB	X-RAY DIFFRACTION	2.6
5C5B	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKG1-F1	81.44	0.54

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 399, 401, 410, 693, 696

Mutagenesis-validated functional residues (1):

Position	Phenotype
410	decreased interaction with ocrl.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-418889	Caspase activation via Dependence Receptors in the absence of ligand

MSigDB gene sets: 461 (showing top): E2F_Q4, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, CREL_01, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_PINOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, E2F4DP1_01, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, AAGTCCA_MIR422B_MIR422A, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_REGULATION_OF_TOLL_LIKE_RECEPTOR_4_SIGNALING_PATHWAY

GO Biological Process (21): protein import into nucleus (GO:0006606), signal transduction (GO:0007165), transforming growth factor beta receptor signaling pathway (GO:0007179), insulin receptor signaling pathway (GO:0008286), regulation of fibroblast migration (GO:0010762), signaling (GO:0023052), adiponectin-activated signaling pathway (GO:0033211), regulation of toll-like receptor 4 signaling pathway (GO:0034143), cellular response to hepatocyte growth factor stimulus (GO:0035729), regulation of innate immune response (GO:0045088), regulation of D-glucose import across plasma membrane (GO:0046324), positive regulation of D-glucose import across plasma membrane (GO:0046326), positive regulation of melanin biosynthetic process (GO:0048023), maintenance of synapse structure (GO:0099558), positive regulation of cytokine production involved in inflammatory response (GO:1900017), regulation of protein localization to plasma membrane (GO:1903076), positive regulation of macropinocytosis (GO:1905303), negative regulation of Fc-gamma receptor signaling pathway involved in phagocytosis (GO:1905450), regulation of G1/S transition of mitotic cell cycle (GO:2000045), positive regulation of biosynthetic process (GO:0009891), positive regulation of transport (GO:0051050)

GO Molecular Function (8): phosphatidylserine binding (GO:0001786), phosphatidylinositol binding (GO:0035091), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein kinase B binding (GO:0043422), protein-containing complex binding (GO:0044877), beta-tubulin binding (GO:0048487), protein binding (GO:0005515)

GO Cellular Component (20): ruffle (GO:0001726), nucleus (GO:0005634), cytoplasm (GO:0005737), endosome (GO:0005768), early endosome (GO:0005769), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), vesicle membrane (GO:0012506), actin cytoskeleton (GO:0015629), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), early endosome membrane (GO:0031901), early phagosome (GO:0032009), macropinosome (GO:0044354), extracellular exosome (GO:0070062), intracellular vesicle (GO:0097708), glutamatergic synapse (GO:0098978), cell projection (GO:0042995), phagocytic vesicle (GO:0045335)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Caspase activation via extrinsic apoptotic signalling pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
D-glucose import across plasma membrane	2
anion binding	2
binding	2
intracellular membrane-bounded organelle	2
intracellular anatomical structure	2
endosome	2
cytoplasm	2
vesicle	2
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
fibroblast migration	1
regulation of cell migration	1
regulation of biological process	1
hormone-mediated signaling pathway	1
cytokine-mediated signaling pathway	1
toll-like receptor 4 signaling pathway	1
regulation of pattern recognition receptor signaling pathway	1
response to hepatocyte growth factor	1
cellular response to growth factor stimulus	1
regulation of response to biotic stimulus	1
regulation of defense response	1
regulation of response to external stimulus	1
innate immune response	1
regulation of immune response	1
regulation of D-glucose transmembrane transport	1
positive regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
melanin biosynthetic process	1

Protein interactions and networks

STRING

2102 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APPL1	RAB5A	P20339	997
APPL1	ADIPOR1	Q96A54	997
APPL1	ADIPOR2	Q86V24	995
APPL1	AKT1	P31749	977
APPL1	IGF1R	P08069	976
APPL1	SRC	P12931	974
APPL1	GIPC1	O14908	961
APPL1	OCRL	Q01968	952
APPL1	AKT2	P31751	900
APPL1	NTRK1	P04629	896
APPL1	ADIPOQ	Q15848	893
APPL1	EEA1	Q15075	820
APPL1	APP	P05067	806
APPL1	EGF	P01133	744
APPL1	RBSN	Q9H1K0	705

IntAct

430 interactions, top by confidence:

A	B	Type	Score
APPL2	APPL1	psi-mi:“MI:0915”(physical association)	0.960
APPL1	APPL2	psi-mi:“MI:0915”(physical association)	0.960
APPL2	APPL1	psi-mi:“MI:0403”(colocalization)	0.960
APPL1	APPL2	psi-mi:“MI:0403”(colocalization)	0.960
APPL1	APPL1	psi-mi:“MI:0915”(physical association)	0.950
APPL1	APPL1	psi-mi:“MI:0407”(direct interaction)	0.950
APPL1	APPL1	psi-mi:“MI:0403”(colocalization)	0.950
APPL1	RAB5A	psi-mi:“MI:0915”(physical association)	0.840
APPL1	RAB5A	psi-mi:“MI:0403”(colocalization)	0.840
RAB5A	APPL1	psi-mi:“MI:0915”(physical association)	0.840
FARS2	APPL1	psi-mi:“MI:0915”(physical association)	0.780
APPL1	FARS2	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (274): APPL1 (Two-hybrid), APPL1 (Two-hybrid), APPL1 (Two-hybrid), APPL1 (Two-hybrid), APPL2 (Two-hybrid), UBE2O (Two-hybrid), RHEBL1 (Two-hybrid), APPL1 (Two-hybrid), APPL1 (Biochemical Activity), APPL1 (Affinity Capture-MS), APPL1 (Affinity Capture-MS), APPL2 (Two-hybrid), APPL1 (Two-hybrid), APPL1 (Affinity Capture-MS), BATF3 (Two-hybrid)

ESM2 similar proteins: A0A098DRQ4, A1A4L0, A1CAN8, A1DF15, A1L1C7, A6RJQ7, A7E559, A7KAL4, B2AVN3, C8VDI2, C8VDQ4, I1RKA1, I1S4N7, O60749, O95219, P0C220, P83094, Q0WQF4, Q2TBW7, Q2U7R4, Q2UB56, Q4IR87, Q4WCV3, Q4WUE5, Q4WZF1, Q524W4, Q5AZC9, Q5R4C2, Q5R6M6, Q5R9A9, Q6NRZ4, Q6P3Q6, Q6PCS4, Q6VVX2, Q7SB54, Q7SB97, Q8J2R3, Q8K3H0, Q8VWF1, Q91VH2

Diamond homologs: B4F779, Q8K3G9, Q8K3H0, Q8NEU8, Q9UKG1

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ADIPOR1	up-regulates	APPL1	binding
ADIPOR2	up-regulates	APPL1	binding
APPL1	up-regulates	STK11	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 117 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Constitutive Signaling by EGFRvIII	5	42.0×	7e-06
Tie2 Signaling	5	35.4×	2e-05
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	33.6×	2e-05
Downstream signal transduction	6	26.9×	7e-06
FLT3 Signaling	6	24.4×	1e-05
Signaling by SCF-KIT	6	17.5×	6e-05
Constitutive Signaling by Aberrant PI3K in Cancer	9	13.4×	4e-06
EPH-ephrin mediated repulsion of cells	5	12.9×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitophagy	6	18.5×	3e-04
autophagosome maturation	5	17.0×	2e-03
epidermal growth factor receptor signaling pathway	6	14.4×	8e-04
cell surface receptor protein tyrosine kinase signaling pathway	8	13.5×	8e-05
positive regulation of protein localization to plasma membrane	5	13.2×	4e-03
Ras protein signal transduction	6	12.0×	2e-03
autophagosome assembly	5	10.9×	7e-03
insulin receptor signaling pathway	5	10.8×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

274 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	125
Likely benign	68
Benign	29

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
208074	NM_012096.3(APPL1):c.1655T>A (p.Leu552Ter)	Pathogenic
1879583	NM_012096.3(APPL1):c.1165C>T (p.Arg389Ter)	Likely pathogenic

SpliceAI

3530 predictions. Top by Δscore:

Variant	Effect	Δscore
3:57227935:CAG:C	donor_loss	1.0000
3:57227938:G:C	donor_loss	1.0000
3:57227939:T:G	donor_loss	1.0000
3:57235562:A:AG	acceptor_gain	1.0000
3:57235563:C:G	acceptor_gain	1.0000
3:57235563:CAGAC:C	acceptor_loss	1.0000
3:57235564:A:AG	acceptor_gain	1.0000
3:57235564:A:T	acceptor_loss	1.0000
3:57235565:G:GT	acceptor_gain	1.0000
3:57235565:GA:G	acceptor_gain	1.0000
3:57235565:GAC:G	acceptor_gain	1.0000
3:57235565:GACA:G	acceptor_gain	1.0000
3:57235565:GACAA:G	acceptor_gain	1.0000
3:57235660:CACAG:C	donor_loss	1.0000
3:57235661:ACAG:A	donor_loss	1.0000
3:57235662:CAGGT:C	donor_loss	1.0000
3:57235663:AGGT:A	donor_loss	1.0000
3:57235664:GGT:G	donor_loss	1.0000
3:57235666:T:G	donor_loss	1.0000
3:57237490:A:AG	acceptor_gain	1.0000
3:57237491:G:GG	acceptor_gain	1.0000
3:57238035:T:A	acceptor_gain	1.0000
3:57238040:TTCA:T	acceptor_loss	1.0000
3:57238043:A:AG	acceptor_gain	1.0000
3:57238043:AGC:A	acceptor_gain	1.0000
3:57238043:AGCG:A	acceptor_loss	1.0000
3:57238044:G:GA	acceptor_gain	1.0000
3:57238044:GC:G	acceptor_gain	1.0000
3:57238044:GCG:G	acceptor_gain	1.0000
3:57238044:GCGT:G	acceptor_gain	1.0000

AlphaMissense

4681 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:57248339:T:C	L284P	1.000
3:57249385:T:A	W297R	1.000
3:57249385:T:C	W297R	1.000
3:57249387:G:C	W297C	1.000
3:57249387:G:T	W297C	1.000
3:57249422:T:C	L309S	1.000
3:57249509:G:C	R338T	1.000
3:57249510:A:C	R338S	1.000
3:57249510:A:T	R338S	1.000
3:57249519:T:G	C341W	1.000
3:57249521:T:C	F342S	1.000
3:57253682:T:A	W366R	1.000
3:57253682:T:C	W366R	1.000
3:57253683:G:C	W366S	1.000
3:57253684:G:C	W366C	1.000
3:57253684:G:T	W366C	1.000
3:57259883:G:C	G508R	1.000
3:57259884:G:A	G508D	1.000
3:57259956:G:C	R532P	1.000
3:57260686:G:A	G585E	1.000
3:57235659:G:C	A50P	0.999
3:57237507:G:C	A57P	0.999
3:57237522:T:C	S62P	0.999
3:57240466:T:C	L96P	0.999
3:57240487:T:C	L103P	0.999
3:57240499:T:C	L107P	0.999
3:57246217:G:C	A206P	0.999
3:57248333:G:A	G282E	0.999
3:57248339:T:A	L284H	0.999
3:57249386:G:C	W297S	0.999

dbSNP variants (sampled 300 via entrez): RS1000005961 (3:57267476 C>G,T), RS1000009301 (3:57265736 C>CT), RS1000063118 (3:57266064 G>A), RS1000130706 (3:57234076 A>G), RS1000182501 (3:57226609 T>C), RS1000227102 (3:57228728 A>G), RS1000371357 (3:57253057 C>T), RS1000531444 (3:57259380 A>G), RS1000552180 (3:57226001 G>A,T), RS1000609895 (3:57272686 G>A,C), RS1000610453 (3:57239292 C>T), RS1000734620 (3:57245971 A>G), RS1000772732 (3:57232661 A>C), RS1001065850 (3:57232229 C>A,T), RS1001099182 (3:57265402 G>A)

Disease associations

OMIM: gene MIM:604299 | disease phenotypes: MIM:616511

GenCC curated gene-disease

Disease	Classification	Inheritance
maturity-onset diabetes of the young type 14	Strong	Autosomal dominant
maturity-onset diabetes of the young	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
monogenic diabetes	Refuted	AD

Mondo (3): maturity-onset diabetes of the young type 14 (MONDO:0014674), monogenic diabetes (MONDO:0015967), maturity-onset diabetes of the young (MONDO:0018911)

Orphanet (2): MODY (Orphanet:552), Rare genetic diabetes mellitus (Orphanet:183625)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000077	Abnormality of the kidney
HP:0000107	Renal cyst
HP:0000112	Nephropathy
HP:0000119	Abnormality of the genitourinary system
HP:0000488	Retinopathy
HP:0000819	Diabetes mellitus
HP:0000825	Hyperinsulinemic hypoglycemia
HP:0000831	Insulin-resistant diabetes mellitus
HP:0000956	Acanthosis nigricans
HP:0001511	Intrauterine growth retardation
HP:0001513	Obesity
HP:0001520	Large for gestational age
HP:0001738	Exocrine pancreatic insufficiency
HP:0001952	Glucose intolerance
HP:0001953	Diabetic ketoacidosis
HP:0001998	Neonatal hypoglycemia
HP:0002594	Pancreatic hypoplasia
HP:0003074	Hyperglycemia
HP:0003076	Glycosuria
HP:0003596	Middle age onset
HP:0004904	Maturity-onset diabetes of the young
HP:0004924	Abnormal oral glucose tolerance
HP:0008255	Transient neonatal diabetes mellitus
HP:0011462	Young adult onset
HP:0012028	Hepatocellular adenoma
HP:0025502	Overweight
HP:0030057	Autoimmune antibody positivity
HP:0030794	Abnormal circulating C-peptide concentration
HP:0040214	Abnormal circulating insulin concentration

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562772	Mason-Type Diabetes (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression	4
sodium arsenite	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
geraniol	decreases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	increases expression	1
tetrabromobisphenol A	decreases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
torcetrapib	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
NSC 689534	affects binding, decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases expression	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression	1
Copper	affects binding, decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1JS	Abcam HeLa APPL1 KO	Cancer cell line	Female
CVCL_E1QP	HAP1 APPL1 (-) 2	Cancer cell line	Male
CVCL_XL41	HAP1 APPL1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

23 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07029009	PHASE2	RECRUITING	Liraglutide Treatment in Patients With Maturity-onset Diabetes of the Young (MODY)
NCT06976658	PHASE2	RECRUITING	Glucokinase Activator in Monogenic Diabetes
NCT01795144	PHASE1	COMPLETED	Incretin Regulation of Insulin Secretion in Monogenic Diabetes
NCT01610934	PHASE2/PHASE3	COMPLETED	The Effects of GLP-1 in Maturity-Onset Diabetes of The Young (MODY)
NCT01342939	Not specified	COMPLETED	Pathophysiological Implications of the Incretin Hormones in Maturity Onset of Diabetes of the Young (MODY)
NCT02082132	Not specified	UNKNOWN	MODY in Young-onset Diabetes in Different Ethnicities
NCT02556840	Not specified	COMPLETED	Impact on Birth Weight of Two Therapeutic Strategies (Insulin Therapy From the Beginning of Pregnancy vs. Insulin Therapy Initiated According to Fetal Growth Evaluated by Ultrasonography Measurements) in Pregnant Women With Monogenic Diabetes
NCT03589092	Not specified	UNKNOWN	Genetic Causes of Gestational Diabetes in the Emirati Population
NCT03607604	Not specified	UNKNOWN	Application of UCPCR as a Testing Tool for Identification of MODY Patients in the UAE
NCT04021199	Not specified	COMPLETED	Screening for Genetic Forms of Diabetes in Convention of Care for Children and Adolescents With Diabetes (GENEPEDIAB)
NCT05586594	Not specified	NOT_YET_RECRUITING	Identifying Maturity-onset Diabetes of the Young in Emirati Patients
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05747118	Not specified	COMPLETED	A Feasibility Study of a 12 Week Training Intervention With Patients With Type 2 Diabetes and MODY in Greenland
NCT05918484	Not specified	COMPLETED	Usefulness of Continuous Glucose Monitoring in MODY Diagnosis
NCT06111833	Not specified	RECRUITING	Optimized Diagnosis and Precision Medicine of MODY
NCT06264427	Not specified	RECRUITING	Phenotypic and Genotypic Characterization of Patients With Dysmetabolism in Greenland
NCT06273059	Not specified	UNKNOWN	Genomic Study of Young-Onset Diabetes Mellitus
NCT07492004	Not specified	RECRUITING	China Monogenic Diabetes Registry
NCT04409795	PHASE2/PHASE3	COMPLETED	Oral Hypoglycemic Therapy for Monogenic Variant Carriers of the Joslin Medalist Study
NCT03988764	Not specified	RECRUITING	Monogenic Diabetes Misdiagnosed as Type 1
NCT06478121	Not specified	RECRUITING	Understanding Beta Cell Disorders Through the Study of Rare Genotypes (ENDURE)
NCT06746610	Not specified	RECRUITING	Screening and Molecular Diagnosis-based Individualized Precision Management of Monogenic Diabetes
NCT07564518	Not specified	NOT_YET_RECRUITING	Application of FreeStyle Libre 2 for Evaluating Glycemic Variability Characteristics in Patients With Extreme Glucose Metabolism Phenotypes