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Database: UniProt
Entry: Q9UKG1
LinkDB: Q9UKG1
Original site: Q9UKG1 
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   29-SEP-2021, entry version 177.
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   SMR; Q9UKG1; -.
DR   BioGRID; 117522; 117.
DR   CORUM; Q9UKG1; -.
DR   DIP; DIP-29322N; -.
DR   ELM; Q9UKG1; -.
DR   IntAct; Q9UKG1; 96.
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; 376 antibodies.
DR   DNASU; 26060; -.
DR   Ensembl; ENST00000288266; ENSP00000288266; ENSG00000157500.
DR   Ensembl; ENST00000650354; ENSP00000498115; ENSG00000157500.
DR   GeneID; 26060; -.
DR   KEGG; hsa:26060; -.
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; NVFRMTE; -.
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; 11 hits in 1019 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 234 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
//
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