DP13A_HUMAN
ID DP13A_HUMAN Reviewed; 709 AA.
AC Q9UKG1; Q9P2B9;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 180.
DE RecName: Full=DCC-interacting protein 13-alpha {ECO:0000305};
DE Short=Dip13-alpha {ECO:0000303|PubMed:12011067};
DE AltName: Full=Adapter protein containing PH domain, PTB domain and leucine zipper motif 1 {ECO:0000305};
GN Name=APPL1 {ECO:0000312|HGNC:HGNC:24035};
GN Synonyms=APPL {ECO:0000312|EMBL:AAH28599.1}, DIP13A,
GN KIAA1428 {ECO:0000312|EMBL:BAA92666.2};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1] {ECO:0000305, ECO:0000312|EMBL:AAF04012.1}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, AND INTERACTION
RP WITH AKT2 AND PIK3CA.
RX PubMed=10490823; DOI=10.1038/sj.onc.1203080;
RA Mitsuuchi Y., Johnson S.W., Sonoda G., Tanno S., Golemis E.A., Testa J.R.;
RT "Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor
RT molecule that interacts with the oncoprotein-serine/threonine kinase
RT AKT2.";
RL Oncogene 18:4891-4898(1999).
RN [2] {ECO:0000305, ECO:0000312|EMBL:AAL17835.1}
RP NUCLEOTIDE SEQUENCE [MRNA], AND INTERACTION WITH DCC.
RX PubMed=12011067; DOI=10.1074/jbc.m204679200;
RA Liu J., Yao F., Wu R., Morgan M., Thorburn A., Finley R.L. Jr., Chen Y.Q.;
RT "Mediation of the DCC apoptotic signal by DIP13 alpha.";
RL J. Biol. Chem. 277:26281-26285(2002).
RN [3] {ECO:0000312|EMBL:BAA92666.2}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain {ECO:0000312|EMBL:BAA92666.2};
RX PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVI. The
RT complete sequences of 150 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 7:65-73(2000).
RN [4]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [5] {ECO:0000312|EMBL:AAH28599.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis {ECO:0000312|EMBL:AAH28599.1};
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RAB5A AND NURD/MECP1
RP COMPLEX, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=15016378; DOI=10.1016/s0092-8674(04)00117-5;
RA Miaczynska M., Christoforidis S., Giner A., Shevchenko A.,
RA Uttenweiler-Joseph S., Habermann B., Wilm M., Parton R.G., Zerial M.;
RT "APPL proteins link Rab5 to nuclear signal transduction via an endosomal
RT compartment.";
RL Cell 116:445-456(2004).
RN [7]
RP INTERACTION WITH OCRL, F&H MOTIF, PHOSPHORYLATION AT SER-410, AND
RP MUTAGENESIS OF SER-410.
RX PubMed=17765681; DOI=10.1016/j.devcel.2007.08.004;
RA Erdmann K.S., Mao Y., McCrea H.J., Zoncu R., Lee S., Paradise S.,
RA Modregger J., Biemesderfer D., Toomre D., De Camilli P.;
RT "A role of the Lowe syndrome protein OCRL in early steps of the endocytic
RT pathway.";
RL Dev. Cell 13:377-390(2007).
RN [8]
RP INTERACTION WITH APPL2.
RX PubMed=17030088; DOI=10.1016/j.mce.2006.08.014;
RA Nechamen C.A., Thomas R.M., Dias J.A.;
RT "APPL1, APPL2, Akt2 and FOXO1a interact with FSHR in a potential signaling
RT complex.";
RL Mol. Cell. Endocrinol. 260:93-99(2007).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E.,
RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y.,
RA Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-399, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP SUBUNIT, INTERACTION WITH APPL2, DOMAIN, AND SUBCELLULAR LOCATION.
RX PubMed=18034774; DOI=10.1111/j.1600-0854.2007.00680.x;
RA Chial H.J., Wu R., Ustach C.V., McPhail L.C., Mobley W.C., Chen Y.Q.;
RT "Membrane targeting by APPL1 and APPL2: dynamic scaffolds that oligomerize
RT and bind phosphoinositides.";
RL Traffic 9:215-229(2008).
RN [12]
RP FUNCTION, AND INTERACTION WITH APPL2.
RX PubMed=19661063; DOI=10.1074/jbc.m109.010355;
RA Wang C., Xin X., Xiang R., Ramos F.J., Liu M., Lee H.J., Chen H., Mao X.,
RA Kikani C.K., Liu F., Dong L.Q.;
RT "Yin-Yang regulation of adiponectin signaling by APPL isoforms in muscle
RT cells.";
RL J. Biol. Chem. 284:31608-31615(2009).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP INTERACTION WITH RUVBL2; CTNNB1; APPL2; HDAC1 AND HDAC2, FUNCTION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=19433865; DOI=10.1074/jbc.m109.007237;
RA Rashid S., Pilecka I., Torun A., Olchowik M., Bielinska B., Miaczynska M.;
RT "Endosomal adaptor proteins APPL1 and APPL2 are novel activators of beta-
RT catenin/TCF-mediated transcription.";
RL J. Biol. Chem. 284:18115-18128(2009).
RN [15]
RP INTERACTION WITH OCRL, AND SUBCELLULAR LOCATION.
RX PubMed=20133602; DOI=10.1073/pnas.0914658107;
RA Swan L.E., Tomasini L., Pirruccello M., Lunardi J., De Camilli P.;
RT "Two closely related endocytic proteins that share a common OCRL-binding
RT motif with APPL1.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:3511-3516(2010).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-401, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP INTERACTION WITH OCRL.
RX PubMed=21233288; DOI=10.1091/mbc.e10-08-0730;
RA Noakes C.J., Lee G., Lowe M.;
RT "The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in
RT the endocytic pathway.";
RL Mol. Biol. Cell 22:606-623(2011).
RN [19]
RP INTERACTION WITH OCRL AND INPP5B, AND F&H MOTIF.
RX PubMed=21666675; DOI=10.1038/nsmb.2071;
RA Pirruccello M., Swan L.E., Folta-Stogniew E., De Camilli P.;
RT "Recognition of the F&H motif by the Lowe syndrome protein OCRL.";
RL Nat. Struct. Mol. Biol. 18:789-795(2011).
RN [20]
RP INTERACTION WITH ANXA2, AND SUBCELLULAR LOCATION.
RX PubMed=21645192; DOI=10.1111/j.1600-0854.2011.01226.x;
RA Urbanska A., Sadowski L., Kalaidzidis Y., Miaczynska M.;
RT "Biochemical characterization of APPL endosomes: the role of annexin A2 in
RT APPL membrane recruitment.";
RL Traffic 12:1227-1241(2011).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [23]
RP FUNCTION.
RX PubMed=24879834; DOI=10.2337/db14-0337;
RA Cheng K.K., Zhu W., Chen B., Wang Y., Wu D., Sweeney G., Wang B., Lam K.S.,
RA Xu A.;
RT "The adaptor protein APPL2 inhibits insulin-stimulated glucose uptake by
RT interacting with TBC1D1 in skeletal muscle.";
RL Diabetes 63:3748-3758(2014).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [25]
RP FUNCTION, INVOLVEMENT IN MODY14, VARIANT MODY14 ASN-94, AND
RP CHARACTERIZATION OF VARIANT MODY14 ASN-94.
RX PubMed=26073777; DOI=10.1016/j.ajhg.2015.05.011;
RA Prudente S., Jungtrakoon P., Marucci A., Ludovico O., Buranasupkajorn P.,
RA Mazza T., Hastings T., Milano T., Morini E., Mercuri L., Bailetti D.,
RA Mendonca C., Alberico F., Basile G., Romani M., Miccinilli E., Pizzuti A.,
RA Carella M., Barbetti F., Pascarella S., Marchetti P., Trischitta V.,
RA Di Paola R., Doria A.;
RT "Loss-of-function mutations in APPL1 in familial diabetes mellitus.";
RL Am. J. Hum. Genet. 97:177-185(2015).
RN [26]
RP INTERACTION WITH TGFBR1 AND PRKCZ, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=26583432; DOI=10.18632/oncotarget.6346;
RA Song J., Mu Y., Li C., Bergh A., Miaczynska M., Heldin C.H., Landstroem M.;
RT "APPL proteins promote TGFbeta-induced nuclear transport of the TGFbeta
RT type I receptor intracellular domain.";
RL Oncotarget 7:279-292(2016).
RN [27]
RP VARIANT [LARGE SCALE ANALYSIS] GLN-643.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Multifunctional adapter protein that binds to various
CC membrane receptors, nuclear factors and signaling proteins to regulate
CC many processes, such as cell proliferation, immune response, endosomal
CC trafficking and cell metabolism (PubMed:26583432, PubMed:15016378,
CC PubMed:26073777, PubMed:19661063, PubMed:10490823). Regulates signaling
CC pathway leading to cell proliferation through interaction with RAB5A
CC and subunits of the NuRD/MeCP1 complex (PubMed:15016378). Functions as
CC a positive regulator of innate immune response via activation of AKT1
CC signaling pathway by forming a complex with APPL1 and PIK3R1 (By
CC similarity). Inhibits Fc-gamma receptor-mediated phagocytosis through
CC PI3K/Akt signaling in macrophages (By similarity). Regulates TLR4
CC signaling in activated macrophages (By similarity). Involved in
CC trafficking of the TGFBR1 from the endosomes to the nucleus via
CC microtubules in a TRAF6-dependent manner (PubMed:26583432). Plays a
CC role in cell metabolism by regulating adiponecting and insulin
CC signaling pathways (PubMed:26073777, PubMed:19661063, PubMed:24879834).
CC Required for fibroblast migration through HGF cell signaling (By
CC similarity). Positive regulator of beta-catenin/TCF-dependent
CC transcription through direct interaction with RUVBL2/reptin resulting
CC in the relief of RUVBL2-mediated repression of beta-catenin/TCF target
CC genes by modulating the interactions within the beta-catenin-reptin-
CC HDAC complex (PubMed:19433865). {ECO:0000250|UniProtKB:Q8K3H0,
CC ECO:0000269|PubMed:10490823, ECO:0000269|PubMed:15016378,
CC ECO:0000269|PubMed:19433865, ECO:0000269|PubMed:19661063,
CC ECO:0000269|PubMed:24879834, ECO:0000269|PubMed:26073777,
CC ECO:0000269|PubMed:26583432}.
CC -!- SUBUNIT: Homodimer (PubMed:18034774). Binds RAB5A/Rab5 through an N-
CC terminal domain. This interaction is essential for its recruitment to
CC endosomal membranes as well as its role in cell proliferation
CC (PubMed:15016378). Binds DCC and the catalytic domain of the inactive
CC form of AKT2 through its PID domain (PubMed:10490823, PubMed:12011067).
CC Binds PIK3CA and subunits of the NuRD/MeCP1 complex (PubMed:10490823,
CC PubMed:15016378). Interacts with OCRL and INPP5B (PubMed:21666675,
CC PubMed:17765681, PubMed:20133602, PubMed:21233288). Interacts with
CC NTRK2 (By similarity). Interacts with APPL2; interaction is independent
CC of follicle stimulating hormone stimulation; interaction is decreased
CC by adiponectin in a time-dependent manner (PubMed:17030088,
CC PubMed:18034774, PubMed:19661063). Forms a complex with APPL2 and
CC RUVBL2 (PubMed:19433865). Forms a complex comprising APPL2, RUVBL2,
CC CTNNB1, HDAC1 and HDAC2; interaction reduces interaction between
CC CTNNB1, HDAC1, HDAC2 and RUVBL2 leading to the decrease of deacetylase
CC activity of this complex; affects the recruitment of repressive
CC complexes to the Wnt target genes (PubMed:19433865). Interacts with
CC ANXA2 (PubMed:21645192). Interacts with TGFBR1; interaction is TGF beta
CC dependent; mediates trafficking of the TGFBR1 from the endosomes to the
CC nucleus via microtubules in a TRAF6-dependent manner (PubMed:26583432).
CC Interacts with PRKCZ (PubMed:26583432). Interacts with PIK3R1 and APPL2
CC (By similarity). Interacts with ADIPOR1; ADIPOQ enhances this
CC interaction; inhibites adiponectin-stimulated binding of APPL2 to
CC ADIPOR1 (By similarity). {ECO:0000250|UniProtKB:Q8K3H0,
CC ECO:0000269|PubMed:10490823, ECO:0000269|PubMed:12011067,
CC ECO:0000269|PubMed:15016378, ECO:0000269|PubMed:17030088,
CC ECO:0000269|PubMed:17765681, ECO:0000269|PubMed:18034774,
CC ECO:0000269|PubMed:19433865, ECO:0000269|PubMed:19661063,
CC ECO:0000269|PubMed:20133602, ECO:0000269|PubMed:21233288,
CC ECO:0000269|PubMed:21645192, ECO:0000269|PubMed:21666675,
CC ECO:0000269|PubMed:26583432}.
CC -!- INTERACTION:
CC Q9UKG1; Q9BV57: ADI1; NbExp=3; IntAct=EBI-741243, EBI-992807;
CC Q9UKG1; Q96A54: ADIPOR1; NbExp=6; IntAct=EBI-741243, EBI-1632076;
CC Q9UKG1; Q9UKG1: APPL1; NbExp=15; IntAct=EBI-741243, EBI-741243;
CC Q9UKG1; Q8NEU8: APPL2; NbExp=19; IntAct=EBI-741243, EBI-741261;
CC Q9UKG1; Q03001: DST; NbExp=3; IntAct=EBI-741243, EBI-310758;
CC Q9UKG1; P00533: EGFR; NbExp=2; IntAct=EBI-741243, EBI-297353;
CC Q9UKG1; O95363: FARS2; NbExp=9; IntAct=EBI-741243, EBI-2513774;
CC Q9UKG1; O15379: HDAC3; NbExp=2; IntAct=EBI-741243, EBI-607682;
CC Q9UKG1; P43362: MAGEA9B; NbExp=4; IntAct=EBI-741243, EBI-10209139;
CC Q9UKG1; P50221: MEOX1; NbExp=3; IntAct=EBI-741243, EBI-2864512;
CC Q9UKG1; Q96PV4: PNMA5; NbExp=3; IntAct=EBI-741243, EBI-10171633;
CC Q9UKG1; Q9UL25: RAB21; NbExp=10; IntAct=EBI-741243, EBI-1056039;
CC Q9UKG1; P20339: RAB5A; NbExp=23; IntAct=EBI-741243, EBI-399437;
CC Q9UKG1; Q8TAI7: RHEBL1; NbExp=3; IntAct=EBI-741243, EBI-746555;
CC Q9UKG1; Q9Y3I0: RTCB; NbExp=3; IntAct=EBI-741243, EBI-2107208;
CC Q9UKG1; Q8WXH0: SYNE2; NbExp=3; IntAct=EBI-741243, EBI-2372294;
CC Q9UKG1; Q05BL1: TP53BP2; NbExp=3; IntAct=EBI-741243, EBI-11952721;
CC Q9UKG1; Q12933: TRAF2; NbExp=3; IntAct=EBI-741243, EBI-355744;
CC Q9UKG1; Q9C0C9: UBE2O; NbExp=6; IntAct=EBI-741243, EBI-2339946;
CC Q9UKG1; Q91VH1: Adipor1; Xeno; NbExp=3; IntAct=EBI-741243, EBI-992398;
CC -!- SUBCELLULAR LOCATION: Early endosome membrane
CC {ECO:0000269|PubMed:15016378, ECO:0000269|PubMed:20133602,
CC ECO:0000269|PubMed:21645192}; Peripheral membrane protein
CC {ECO:0000269|PubMed:15016378}. Nucleus {ECO:0000269|PubMed:15016378,
CC ECO:0000269|PubMed:19433865, ECO:0000269|PubMed:26583432}. Cytoplasm
CC {ECO:0000269|PubMed:19433865, ECO:0000269|PubMed:19661063}. Endosome
CC {ECO:0000269|PubMed:26583432}. Cell projection, ruffle
CC {ECO:0000250|UniProtKB:Q8K3H0}. Cytoplasmic vesicle, phagosome
CC {ECO:0000250|UniProtKB:Q8K3H0}. Note=Early endosomal membrane-bound and
CC nuclear. Translocated into the nucleus upon release from endosomal
CC membranes following internalization of EGF.
CC {ECO:0000269|PubMed:15016378}.
CC -!- TISSUE SPECIFICITY: High levels in heart, ovary, pancreas and skeletal
CC muscle. {ECO:0000269|PubMed:10490823}.
CC -!- DOMAIN: Overexpression of an N-terminal domain (residues 1-319) or a C-
CC terminal region (residues 273-709) has a proapoptotic effect.
CC {ECO:0000269|PubMed:15016378}.
CC -!- DOMAIN: The F&H motif, an approximately 12-13 amino-acid sequence
CC centered around Phe and His residues, is essential for binding to OCRL
CC and INPP5B. {ECO:0000269|PubMed:21666675}.
CC -!- PTM: Phosphorylation at Ser-410 by PKA severely impairs binding to
CC OCRL. {ECO:0000269|PubMed:17765681}.
CC -!- DISEASE: Maturity-onset diabetes of the young 14 (MODY14) [MIM:616511]:
CC A form of diabetes that is characterized by an autosomal dominant mode
CC of inheritance, onset in childhood or early adulthood (usually before
CC 25 years of age), a primary defect in insulin secretion and frequent
CC insulin-independence at the beginning of the disease.
CC {ECO:0000269|PubMed:26073777}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
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DR EMBL; AF169797; AAF04012.1; -; mRNA.
DR EMBL; AF424738; AAL17835.1; -; mRNA.
DR EMBL; AB037849; BAA92666.2; -; mRNA.
DR EMBL; BC028599; AAH28599.1; -; mRNA.
DR CCDS; CCDS2882.1; -.
DR RefSeq; NP_036228.1; NM_012096.2.
DR PDB; 2EJ8; X-ray; 1.84 A; A/B=492-644.
DR PDB; 2ELA; X-ray; 2.00 A; A/B=493-646.
DR PDB; 2ELB; X-ray; 2.60 A; A=1-376.
DR PDB; 2Q12; X-ray; 1.79 A; A=5-265.
DR PDB; 2Q13; X-ray; 2.05 A; A=5-385.
DR PDB; 2Z0N; X-ray; 1.95 A; A=1-275.
DR PDB; 2Z0O; X-ray; 2.58 A; A=1-385.
DR PDB; 5C5B; X-ray; 2.90 A; A/C=5-375.
DR PDBsum; 2EJ8; -.
DR PDBsum; 2ELA; -.
DR PDBsum; 2ELB; -.
DR PDBsum; 2Q12; -.
DR PDBsum; 2Q13; -.
DR PDBsum; 2Z0N; -.
DR PDBsum; 2Z0O; -.
DR PDBsum; 5C5B; -.
DR AlphaFoldDB; Q9UKG1; -.
DR SMR; Q9UKG1; -.
DR BioGRID; 117522; 133.
DR CORUM; Q9UKG1; -.
DR DIP; DIP-29322N; -.
DR ELM; Q9UKG1; -.
DR IntAct; Q9UKG1; 98.
DR MINT; Q9UKG1; -.
DR STRING; 9606.ENSP00000288266; -.
DR MoonDB; Q9UKG1; Curated.
DR GlyGen; Q9UKG1; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9UKG1; -.
DR PhosphoSitePlus; Q9UKG1; -.
DR BioMuta; APPL1; -.
DR DMDM; 61213025; -.
DR EPD; Q9UKG1; -.
DR jPOST; Q9UKG1; -.
DR MassIVE; Q9UKG1; -.
DR MaxQB; Q9UKG1; -.
DR PaxDb; Q9UKG1; -.
DR PeptideAtlas; Q9UKG1; -.
DR PRIDE; Q9UKG1; -.
DR ProteomicsDB; 84785; -.
DR Antibodypedia; 2775; 391 antibodies from 37 providers.
DR DNASU; 26060; -.
DR Ensembl; ENST00000288266.8; ENSP00000288266.3; ENSG00000157500.12.
DR Ensembl; ENST00000650354.1; ENSP00000498115.1; ENSG00000157500.12.
DR GeneID; 26060; -.
DR KEGG; hsa:26060; -.
DR MANE-Select; ENST00000288266.8; ENSP00000288266.3; NM_012096.3; NP_036228.1.
DR UCSC; uc003dio.4; human.
DR CTD; 26060; -.
DR DisGeNET; 26060; -.
DR GeneCards; APPL1; -.
DR GeneReviews; APPL1; -.
DR HGNC; HGNC:24035; APPL1.
DR HPA; ENSG00000157500; Low tissue specificity.
DR MalaCards; APPL1; -.
DR MIM; 604299; gene.
DR MIM; 616511; phenotype.
DR neXtProt; NX_Q9UKG1; -.
DR OpenTargets; ENSG00000157500; -.
DR Orphanet; 552; MODY.
DR PharmGKB; PA162376755; -.
DR VEuPathDB; HostDB:ENSG00000157500; -.
DR eggNOG; KOG0521; Eukaryota.
DR eggNOG; KOG3536; Eukaryota.
DR GeneTree; ENSGT00940000156624; -.
DR HOGENOM; CLU_025935_0_0_1; -.
DR InParanoid; Q9UKG1; -.
DR OMA; XVRREMD; -.
DR OrthoDB; 253010at2759; -.
DR PhylomeDB; Q9UKG1; -.
DR TreeFam; TF328669; -.
DR PathwayCommons; Q9UKG1; -.
DR Reactome; R-HSA-418889; Caspase activation via Dependence Receptors in the absence of ligand.
DR SignaLink; Q9UKG1; -.
DR SIGNOR; Q9UKG1; -.
DR BioGRID-ORCS; 26060; 14 hits in 1078 CRISPR screens.
DR ChiTaRS; APPL1; human.
DR EvolutionaryTrace; Q9UKG1; -.
DR GeneWiki; APPL1; -.
DR GenomeRNAi; 26060; -.
DR Pharos; Q9UKG1; Tbio.
DR PRO; PR:Q9UKG1; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q9UKG1; protein.
DR Bgee; ENSG00000157500; Expressed in calcaneal tendon and 195 other tissues.
DR ExpressionAtlas; Q9UKG1; baseline and differential.
DR Genevisible; Q9UKG1; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:BHF-UCL.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0032009; C:early phagosome; ISS:UniProtKB.
DR GO; GO:0005768; C:endosome; IDA:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0097708; C:intracellular vesicle; IDA:UniProtKB.
DR GO; GO:0044354; C:macropinosome; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0001726; C:ruffle; ISS:UniProtKB.
DR GO; GO:0012506; C:vesicle membrane; IDA:BHF-UCL.
DR GO; GO:0048487; F:beta-tubulin binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0035091; F:phosphatidylinositol binding; IDA:UniProtKB.
DR GO; GO:0001786; F:phosphatidylserine binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0043422; F:protein kinase B binding; IPI:BHF-UCL.
DR GO; GO:0044877; F:protein-containing complex binding; IPI:UniProtKB.
DR GO; GO:0033211; P:adiponectin-activated signaling pathway; IMP:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0035729; P:cellular response to hepatocyte growth factor stimulus; ISS:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:1905450; P:negative regulation of Fc-gamma receptor signaling pathway involved in phagocytosis; ISS:UniProtKB.
DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; ISS:UniProtKB.
DR GO; GO:0046326; P:positive regulation of glucose import; IMP:UniProtKB.
DR GO; GO:1905303; P:positive regulation of macropinocytosis; ISS:UniProtKB.
DR GO; GO:0048023; P:positive regulation of melanin biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006606; P:protein import into nucleus; IDA:UniProtKB.
DR GO; GO:0010762; P:regulation of fibroblast migration; ISS:UniProtKB.
DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; IDA:UniProtKB.
DR GO; GO:0046324; P:regulation of glucose import; IMP:BHF-UCL.
DR GO; GO:0045088; P:regulation of innate immune response; ISS:UniProtKB.
DR GO; GO:1903076; P:regulation of protein localization to plasma membrane; IMP:BHF-UCL.
DR GO; GO:0034143; P:regulation of toll-like receptor 4 signaling pathway; ISS:UniProtKB.
DR GO; GO:0007165; P:signal transduction; TAS:UniProtKB.
DR GO; GO:0023052; P:signaling; IBA:GO_Central.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IMP:UniProtKB.
DR CDD; cd07631; BAR_APPL1; 1.
DR Gene3D; 1.20.1270.60; -; 1.
DR Gene3D; 2.30.29.30; -; 2.
DR InterPro; IPR027267; AH/BAR_dom_sf.
DR InterPro; IPR037929; APPL1_BAR.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR006020; PTB/PI_dom.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF00640; PID; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00462; PTB; 1.
DR SUPFAM; SSF103657; SSF103657; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS01179; PID; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell cycle; Cell projection; Coiled coil; Cytoplasm;
KW Cytoplasmic vesicle; Diabetes mellitus; Disease variant; Endosome;
KW Membrane; Nucleus; Phosphoprotein; Reference proteome.
FT CHAIN 1..709
FT /note="DCC-interacting protein 13-alpha"
FT /id="PRO_0000079985"
FT DOMAIN 3..268
FT /note="BAR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00361"
FT DOMAIN 277..375
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 496..656
FT /note="PID"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT REGION 1..428
FT /note="Required for RAB5A binding"
FT REGION 397..434
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 467..491
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 645..709
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 215..259
FT /evidence="ECO:0000255"
FT COILED 621..673
FT /evidence="ECO:0000255"
FT MOTIF 403..414
FT /note="F&H"
FT COMPBIAS 397..412
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 419..434
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 645..668
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 670..696
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 399
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 401
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231"
FT MOD_RES 410
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000269|PubMed:17765681"
FT MOD_RES 693
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8K3H0"
FT MOD_RES 696
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8K3H0"
FT VARIANT 94
FT /note="D -> N (in MODY14; no effect on protein abundance;
FT loss of function in insulin receptor signaling pathway;
FT dbSNP:rs796065047)"
FT /evidence="ECO:0000269|PubMed:26073777"
FT /id="VAR_075857"
FT VARIANT 108
FT /note="A -> V (in dbSNP:rs4381906)"
FT /id="VAR_050958"
FT VARIANT 643
FT /note="E -> Q (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035909"
FT VARIANT 700
FT /note="E -> G (in dbSNP:rs11544593)"
FT /id="VAR_050959"
FT MUTAGEN 410
FT /note="S->D: Decreased interaction with OCRL."
FT /evidence="ECO:0000269|PubMed:17765681"
FT HELIX 9..11
FT /evidence="ECO:0007829|PDB:2Q13"
FT TURN 12..14
FT /evidence="ECO:0007829|PDB:2Q13"
FT HELIX 16..66
FT /evidence="ECO:0007829|PDB:2Q12"
FT HELIX 67..70
FT /evidence="ECO:0007829|PDB:2Q12"
FT HELIX 81..110
FT /evidence="ECO:0007829|PDB:2Q12"
FT HELIX 112..120
FT /evidence="ECO:0007829|PDB:2Q12"
FT HELIX 122..151
FT /evidence="ECO:0007829|PDB:2Q12"
FT STRAND 152..154
FT /evidence="ECO:0007829|PDB:2Q13"
FT HELIX 157..217
FT /evidence="ECO:0007829|PDB:2Q12"
FT HELIX 220..257
FT /evidence="ECO:0007829|PDB:2Q12"
FT HELIX 259..261
FT /evidence="ECO:0007829|PDB:2Q13"
FT STRAND 262..265
FT /evidence="ECO:0007829|PDB:2Q13"
FT TURN 268..270
FT /evidence="ECO:0007829|PDB:2Q13"
FT STRAND 281..286
FT /evidence="ECO:0007829|PDB:2Q13"
FT STRAND 298..305
FT /evidence="ECO:0007829|PDB:2Q13"
FT STRAND 308..312
FT /evidence="ECO:0007829|PDB:2Q13"
FT STRAND 320..324
FT /evidence="ECO:0007829|PDB:2Q13"
FT STRAND 329..333
FT /evidence="ECO:0007829|PDB:2Q13"
FT STRAND 339..345
FT /evidence="ECO:0007829|PDB:2Q13"
FT STRAND 348..350
FT /evidence="ECO:0007829|PDB:2ELB"
FT STRAND 354..356
FT /evidence="ECO:0007829|PDB:5C5B"
FT HELIX 360..374
FT /evidence="ECO:0007829|PDB:2Q13"
FT STRAND 499..512
FT /evidence="ECO:0007829|PDB:2EJ8"
FT HELIX 519..534
FT /evidence="ECO:0007829|PDB:2EJ8"
FT STRAND 542..555
FT /evidence="ECO:0007829|PDB:2EJ8"
FT TURN 557..559
FT /evidence="ECO:0007829|PDB:2EJ8"
FT STRAND 562..567
FT /evidence="ECO:0007829|PDB:2EJ8"
FT HELIX 568..570
FT /evidence="ECO:0007829|PDB:2EJ8"
FT STRAND 571..577
FT /evidence="ECO:0007829|PDB:2EJ8"
FT STRAND 580..590
FT /evidence="ECO:0007829|PDB:2EJ8"
FT STRAND 600..610
FT /evidence="ECO:0007829|PDB:2EJ8"
FT HELIX 612..629
FT /evidence="ECO:0007829|PDB:2EJ8"
FT HELIX 634..643
FT /evidence="ECO:0007829|PDB:2ELA"
SQ SEQUENCE 709 AA; 79663 MW; 4CABECFCF4BB110D CRC64;
MPGIDKLPIE ETLEDSPQTR SLLGVFEEDA TAISNYMNQL YQAMHRIYDA QNELSAATHL
TSKLLKEYEK QRFPLGGDDE VMSSTLQQFS KVIDELSSCH AVLSTQLADA MMFPITQFKE
RDLKEILTLK EVFQIASNDH DAAINRYSRL SKKRENDKVK YEVTEDVYTS RKKQHQTMMH
YFCALNTLQY KKKIALLEPL LGYMQAQISF FKMGSENLNE QLEEFLANIG TSVQNVRREM
DSDIETMQQT IEDLEVASDP LYVPDPDPTK FPVNRNLTRK AGYLNARNKT GLVSSTWDRQ
FYFTQGGNLM SQARGDVAGG LAMDIDNCSV MAVDCEDRRY CFQITSFDGK KSSILQAESK
KDHEEWICTI NNISKQIYLS ENPEETAARV NQSALEAVTP SPSFQQRHES LRPAAGQSRP
PTARTSSSGS LGSESTNLAA LSLDSLVAPD TPIQFDIISP VCEDQPGQAK AFGQGGRRTN
PFGESGGSTK SETEDSILHQ LFIVRFLGSM EVKSDDHPDV VYETMRQILA ARAIHNIFRM
TESHLLVTCD CLKLIDPQTQ VTRLTFPLPC VVLYATHQEN KRLFGFVLRT SSGRSESNLS
SVCYIFESNN EGEKICDSVG LAKQIALHAE LDRRASEKQK EIERVKEKQQ KELNKQKQIE
KDLEEQSRLI AASSRPNQAS SEGQFVVLSS SQSEESDLGE GGKKRESEA
