APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1)

Gene

• Entrez ID: 26060
• Gene name: Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1
• Gene symbol: APPL1
• Synonyms: APPL, DIP13alpha, MODY14
• Chromosome: 3
• Chromosome location: 3p14.3
• Summary: 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. [provided by RefSeq, Jul 2008]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs796065047	G>A	Pathogenic	Missense variant, coding sequence variant
rs869320673	T>A	Pathogenic	Stop gained, coding sequence variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT019612	hsa-miR-340-5p	Sequencing	20371350
MIRT024351	hsa-miR-215-5p	Microarray	19074876
MIRT026723	hsa-miR-192-5p	Microarray	19074876
MIRT027894	hsa-miR-96-5p	Sequencing	20371350
MIRT028333	hsa-miR-32-5p	Sequencing	20371350
MIRT028333	hsa-miR-32-5p	HITS-CLIP	22473208
MIRT030980	hsa-miR-21-5p	Microarray	18591254
MIRT030980	hsa-miR-21-5p	HITS-CLIP	22473208
MIRT037107	hsa-miR-877-3p	CLASH	23622248
MIRT042464	hsa-miR-423-3p	CLASH	23622248
MIRT042832	hsa-miR-324-3p	CLASH	23622248
MIRT051527	hsa-let-7e-5p	CLASH	23622248
MIRT051903	hsa-let-7b-5p	CLASH	23622248
MIRT092387	hsa-miR-92a-3p	HITS-CLIP	22473208
MIRT092391	hsa-miR-92b-3p	HITS-CLIP	22473208
MIRT092423	hsa-miR-3609	HITS-CLIP	23824327
MIRT092424	hsa-miR-548ah-5p	HITS-CLIP	23824327
MIRT210447	hsa-miR-3148	PAR-CLIP	22100165
MIRT450341	hsa-miR-526b-5p	PAR-CLIP	22100165
MIRT624706	hsa-miR-335-3p	HITS-CLIP	23824327
MIRT624707	hsa-miR-664b-3p	HITS-CLIP	23824327
MIRT624708	hsa-miR-579-3p	HITS-CLIP	23824327
MIRT624709	hsa-miR-5696	HITS-CLIP	23824327
MIRT624710	hsa-miR-6820-3p	HITS-CLIP	23824327
MIRT624711	hsa-miR-3164	HITS-CLIP	23824327
MIRT624712	hsa-miR-1250-3p	HITS-CLIP	23824327
MIRT629121	hsa-miR-2909	HITS-CLIP	23824327
MIRT629121	hsa-miR-2909	HITS-CLIP	23313552
MIRT629122	hsa-miR-7977	HITS-CLIP	23824327
MIRT629122	hsa-miR-7977	HITS-CLIP	23313552
MIRT629123	hsa-miR-1296-5p	HITS-CLIP	23824327
MIRT629123	hsa-miR-1296-5p	HITS-CLIP	23313552
MIRT629124	hsa-miR-6781-5p	HITS-CLIP	23824327
MIRT629124	hsa-miR-6781-5p	HITS-CLIP	23313552
MIRT629125	hsa-miR-24-3p	HITS-CLIP	23824327
MIRT629125	hsa-miR-24-3p	HITS-CLIP	23313552
MIRT629126	hsa-miR-4284	HITS-CLIP	23824327
MIRT629126	hsa-miR-4284	HITS-CLIP	23313552
MIRT629127	hsa-miR-564	HITS-CLIP	23824327
MIRT629127	hsa-miR-564	HITS-CLIP	23313552
MIRT629128	hsa-miR-4512	HITS-CLIP	23824327
MIRT629128	hsa-miR-4512	HITS-CLIP	23313552
MIRT629129	hsa-miR-7160-3p	HITS-CLIP	23824327
MIRT629129	hsa-miR-7160-3p	HITS-CLIP	23313552
MIRT629130	hsa-miR-6895-5p	HITS-CLIP	23824327
MIRT629130	hsa-miR-6895-5p	HITS-CLIP	23313552

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0001726	Component	Ruffle	ISS
GO:0001786	Function	Phosphatidylserine binding	IDA	18034774
GO:0005515	Function	Protein binding	IPI	10490823, 12011067, 15016378, 16189514, 16273093, 16622416, 17030088, 17581628, 18034774, 19433865, 19661063, 21233288, 21291857, 21645192, 23414517, 23752268, 24879834, 25241761, 25416956, 25814554, 26583432, 28514442, 29568061, 31515488, 32296183
GO:0005634	Component	Nucleus	IDA	15016378, 18034774, 19433865, 26583432
GO:0005737	Component	Cytoplasm	IDA	19433865, 19661063, 21291857
GO:0005768	Component	Endosome	IDA	26583432
GO:0005769	Component	Early endosome	IDA	21645192
GO:0005769	Component	Early endosome	ISS
GO:0005829	Component	Cytosol	IDA	17848569
GO:0005886	Component	Plasma membrane	IDA	18034774
GO:0006606	Process	Protein import into nucleus	IDA	26583432
GO:0007049	Process	Cell cycle	IEA
GO:0007165	Process	Signal transduction	TAS	10490823
GO:0007179	Process	Transforming growth factor beta receptor signaling pathway	IMP	26583432
GO:0008286	Process	Insulin receptor signaling pathway	IBA	21873635
GO:0008286	Process	Insulin receptor signaling pathway	IMP	26073777
GO:0008286	Process	Insulin receptor signaling pathway	TAS	17848569
GO:0010008	Component	Endosome membrane	IBA	21873635
GO:0010008	Component	Endosome membrane	IDA	15016378
GO:0010008	Component	Endosome membrane	TAS
GO:0010762	Process	Regulation of fibroblast migration	ISS
GO:0012506	Component	Vesicle membrane	IDA	17848569
GO:0016020	Component	Membrane	IDA	18034774
GO:0023052	Process	Signaling	IBA	21873635
GO:0031410	Component	Cytoplasmic vesicle	IDA	18034774
GO:0031901	Component	Early endosome membrane	IEA
GO:0032009	Component	Early phagosome	ISS
GO:0033211	Process	Adiponectin-activated signaling pathway	IMP	19661063
GO:0034143	Process	Regulation of toll-like receptor 4 signaling pathway	ISS
GO:0035091	Function	Phosphatidylinositol binding	IDA	18034774
GO:0035729	Process	Cellular response to hepatocyte growth factor stimulus	ISS
GO:0042802	Function	Identical protein binding	IPI	17502098, 17581628, 18034774, 25416956, 31515488, 32296183
GO:0042803	Function	Protein homodimerization activity	IDA	18034774
GO:0043422	Function	Protein kinase B binding	IBA	21873635
GO:0043422	Function	Protein kinase B binding	IPI	17848569
GO:0044354	Component	Macropinosome	ISS
GO:0044877	Function	Protein-containing complex binding	IPI	15016378
GO:0045088	Process	Regulation of innate immune response	ISS
GO:0046324	Process	Regulation of glucose import	IMP	17848569
GO:0046326	Process	Positive regulation of glucose import	IMP	24879834
GO:0048023	Process	Positive regulation of melanin biosynthetic process	IMP	21291857
GO:0048487	Function	Beta-tubulin binding	IDA	26583432
GO:0070062	Component	Extracellular exosome	HDA	18570454, 19056867
GO:0097192	Process	Extrinsic apoptotic signaling pathway in absence of ligand	TAS
GO:0097708	Component	Intracellular vesicle	IDA	21291857
GO:1900017	Process	Positive regulation of cytokine production involved in inflammatory response	ISS
GO:1903076	Process	Regulation of protein localization to plasma membrane	IMP	17848569
GO:1905303	Process	Positive regulation of macropinocytosis	ISS
GO:1905450	Process	Negative regulation of Fc-gamma receptor signaling pathway involved in phagocytosis	ISS
GO:2000045	Process	Regulation of G1/S transition of mitotic cell cycle	IDA	15016378

Other IDs

• MIM: 604299
• HGNC: 24035
• e!Ensembl: ENSG00000157500

Protein

• UniProt ID: Q9UKG1
• Protein name: DCC-interacting protein 13-alpha (Dip13-alpha) (Adapter protein containing PH domain, PTB domain and leucine zipper motif 1)
• Protein 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 (PubMed:26583432, PubMed:15016378, PubMed:26073777, PubMed:19661063, PubMed:10490823). Regulates signaling pathway leading to cell proliferation through interaction with RAB5A and subunits of the NuRD/MeCP1 complex (PubMed:15016378). Functions as a positive regulator of innate immune response via activation of AKT1 signaling pathway by forming a complex with APPL1 and PIK3R1 (By similarity). Inhibits Fc-gamma receptor-mediated phagocytosis through PI3K/Akt signaling in macrophages (By similarity). Regulates TLR4 signaling in activated macrophages (By similarity). Involved in trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner (PubMed:26583432). Plays a role in cell metabolism by regulating adiponecting and insulin signaling pathways (PubMed:26073777, PubMed:19661063, PubMed:24879834). Required for fibroblast migration through HGF cell signaling (By similarity). 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 (PubMed:19433865).
• PDB: 2EJ8, 2ELA, 2ELB, 2Q12, 2Q13, 2Z0N, 2Z0O, 5C5B
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF16746	BAR_3	7 → 247		Domain
  PF00169	PH	278 → 375	PH domain	Domain
  PF00640	PID	502 → 633	Phosphotyrosine interaction domain (PTB/PID)	Domain

• Sequence:

  MPGIDKLPIEETLEDSPQTRSLLGVFEEDATAISNYMNQLYQAMHRIYDAQNELSAATHL
  TSKLLKEYEKQRFPLGGDDEVMSSTLQQFSKVIDELSSCHAVLSTQLADAMMFPITQFKE
  RDLKEILTLKEVFQIASNDHDAAINRYSRLSKKRENDKVKYEVTEDVYTSRKKQHQTMMH
  YFCALNTLQYKKKIALLEPLLGYMQAQISFFKMGSENLNEQLEEFLANIGTSVQNVRREM
  DSDIETMQQTIEDLEVASDPLYVPDPDPTKFPVNRNLTRKAGYLNARNKTGLVSSTWDRQ
  FYFTQGGNLMSQARGDVAGGLAMDIDNCSVMAVDCEDRRYCFQITSFDGKKSSILQAESK
  KDHEEWICTINNISKQIYLSENPEETAARVNQSALEAVTPSPSFQQRHESLRPAAGQSRP
  PTARTSSSGSLGSESTNLAALSLDSLVAPDTPIQFDIISPVCEDQPGQAKAFGQGGRRTN
  PFGESGGSTKSETEDSILHQLFIVRFLGSMEVKSDDHPDVVYETMRQILAARAIHNIFRM
  TESHLLVTCDCLKLIDPQTQVTRLTFPLPCVVLYATHQENKRLFGFVLRTSSGRSESNLS
  SVCYIFESNNEGEKICDSVGLAKQIALHAELDRRASEKQKEIERVKEKQQKELNKQKQIE
  KDLEEQSRLIAASSRPNQASSEGQFVVLSSSQSEESDLGEGGKKRESEA

• Sequence length: 709