ID   DEND3_HUMAN             Reviewed;        1198 AA.
AC   A2RUS2; B7ZM28; O94947; Q2TAM7; Q6ZMS6; Q96DK3;
DT   11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
DT   11-SEP-2007, sequence version 2.
DT   04-NOV-2026, entry version 145.
DE   RecName: Full=DENN domain-containing protein 3;
GN   Name=DENND3; Synonyms=KIAA0870;
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]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4).
RC   TISSUE=Gastric mucosa, and Uterus;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16421571; DOI=10.1038/nature04406;
RA   Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA   Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA   Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA   Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA   Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA   Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA   Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA   Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA   Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA   O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA   Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA   Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA   Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA   Platzer M., Shimizu N., Lander E.S.;
RT   "DNA sequence and analysis of human chromosome 8.";
RL   Nature 439:331-335(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Brain;
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   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 180-1146 (ISOFORM 1).
RC   TISSUE=Brain;
RX   PubMed=10048485; DOI=10.1093/dnares/5.6.355;
RA   Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N.,
RA   Tanaka A., Kotani H., Nomura N., Ohara O.;
RT   "Prediction of the coding sequences of unidentified human genes. XII. The
RT   complete sequences of 100 new cDNA clones from brain which code for large
RT   proteins in vitro.";
RL   DNA Res. 5:355-364(1998).
RN   [5]
RP   FUNCTION AS GUANYL-NUCLEOTIDE EXCHANGE FACTOR.
RX   PubMed=20937701; DOI=10.1083/jcb.201008051;
RA   Yoshimura S., Gerondopoulos A., Linford A., Rigden D.J., Barr F.A.;
RT   "Family-wide characterization of the DENN domain Rab GDP-GTP exchange
RT   factors.";
RL   J. Cell Biol. 191:367-381(2010).
CC   -!- FUNCTION: Guanine nucleotide exchange factor (GEF) activating RAB12.
CC       Promotes the exchange of GDP to GTP, converting inactive GDP-bound
CC       RAB12 into its active GTP-bound form (PubMed:20937701). Regulates
CC       autophagy in response to starvation through RAB12 activation.
CC       Starvation leads to ULK1/2-dependent phosphorylation of Ser-472 and
CC       Ser-490, which in turn allows recruitment of 14-3-3 adapter proteins
CC       and leads to up-regulation of GEF activity towards RAB12 (By
CC       similarity). Also plays a role in protein transport from recycling
CC       endosomes to lysosomes, regulating, for instance, the degradation of
CC       the transferrin receptor and of the amino acid transporter PAT4
CC       (PubMed:20937701). Starvation also induces phosphorylation at Tyr-858,
CC       which leads to up-regulated GEF activity and initiates autophagy (By
CC       similarity). {ECO:0000250|UniProtKB:A2RT67,
CC       ECO:0000269|PubMed:20937701}.
CC   -!- SUBUNIT: Forms oligomers. Interacts with 6 of the 7 known isoforms of
CC       14-3-3 proteins. {ECO:0000250|UniProtKB:A2RT67}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:A2RT67}.
CC       Note=Transiently recruited to membranes to activate RAB12.
CC       {ECO:0000250|UniProtKB:A2RT67}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=4;
CC       Name=1;
CC         IsoId=A2RUS2-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=A2RUS2-2; Sequence=VSP_028080;
CC       Name=3;
CC         IsoId=A2RUS2-3; Sequence=VSP_028075, VSP_028081;
CC       Name=4;
CC         IsoId=A2RUS2-4; Sequence=VSP_028077, VSP_028078;
CC   -!- DOMAIN: Inactive DENND3 is found in a closed conformation, in which the
CC       linker region interacts with the DENN domain. Phosphorylation of Tyr-
CC       858 in the linker region interferes with this interaction leading to an
CC       open conformation and enhances the GEF activity of the protein towards
CC       RAB12. {ECO:0000250|UniProtKB:A2RT67}.
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DR   EMBL; AK058001; BAB71630.1; -; mRNA.
DR   EMBL; AK131505; BAD18649.1; -; mRNA.
DR   EMBL; AC040970; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC133023; AAI33024.1; -; mRNA.
DR   EMBL; BC144226; AAI44227.1; -; mRNA.
DR   EMBL; AB020677; BAA74893.2; -; mRNA.
DR   RefSeq; NP_055772.3; NM_014957.5.
DR   AlphaFoldDB; A2RUS2; -.
DR   SMR; A2RUS2; -.
DR   BioGRID; 116562; 8.
DR   FunCoup; A2RUS2; 959.
DR   IntAct; A2RUS2; 9.
DR   STRING; 9606.ENSP00000428714; -.
DR   GlyCosmos; A2RUS2; 3 sites, 1 glycan.
DR   GlyGen; A2RUS2; 3 sites, 1 O-linked glycan (3 sites).
DR   iPTMnet; A2RUS2; -.
DR   PhosphoSitePlus; A2RUS2; -.
DR   BioMuta; DENND3; -.
DR   jPOST; A2RUS2; -.
DR   MassIVE; A2RUS2; -.
DR   PaxDb; 9606-ENSP00000428714; -.
DR   PeptideAtlas; A2RUS2; -.
DR   ProteomicsDB; 519; -. [A2RUS2-1]
DR   ProteomicsDB; 520; -. [A2RUS2-2]
DR   ProteomicsDB; 521; -. [A2RUS2-3]
DR   ProteomicsDB; 522; -. [A2RUS2-4]
DR   Pumba; A2RUS2; -.
DR   Antibodypedia; 27680; 42 antibodies from 16 providers.
DR   DNASU; 22898; -.
DR   Ensembl; ENST00000262585.6; ENSP00000262585.2; ENSG00000105339.12. [A2RUS2-1]
DR   Ensembl; ENST00000424248.2; ENSP00000410594.1; ENSG00000105339.12. [A2RUS2-2]
DR   GeneID; 22898; -.
DR   KEGG; hsa:22898; -.
DR   UCSC; uc003yvy.4; human. [A2RUS2-1]
DR   AGR; HGNC:29134; -.
DR   ClinPGx; PA142671987; -.
DR   CTD; 22898; -.
DR   DisGeNET; 22898; -.
DR   GeneCards; DENND3; -.
DR   HGNC; HGNC:29134; DENND3.
DR   HPA; ENSG00000105339; Tissue enhanced (bone).
DR   MalaCards; DENND3; -.
DR   MIM; 617503; gene.
DR   OpenTargets; ENSG00000105339; -.
DR   VEuPathDB; HostDB:ENSG00000105339; -.
DR   eggNOG; KOG2127; Eukaryota.
DR   GeneTree; ENSGT00940000155784; -.
DR   HOGENOM; CLU_280008_0_0_1; -.
DR   InParanoid; A2RUS2; -.
DR   OrthoDB; 6019893at2759; -.
DR   PAN-GO; A2RUS2; 4 GO annotations based on evolutionary models.
DR   PhylomeDB; A2RUS2; -.
DR   PathwayCommons; A2RUS2; -.
DR   Reactome; R-HSA-8876198; RAB GEFs exchange GTP for GDP on RABs.
DR   SignaLink; A2RUS2; -.
DR   SIGNOR; A2RUS2; -.
DR   Agora; ENSG00000105339; -.
DR   BioGRID-ORCS; 22898; 12 hits in 1151 CRISPR screens.
DR   ChiTaRS; DENND3; human.
DR   GenomeRNAi; 22898; -.
DR   Pharos; A2RUS2; Tbio.
DR   PRO; PR:A2RUS2; -.
DR   Proteomes; UP000005640; Chromosome 8.
DR   RNAct; A2RUS2; protein.
DR   Bgee; ENSG00000105339; Expressed in right lung and 155 other cell types or tissues.
DR   ExpressionAtlas; A2RUS2; baseline and differential.
DR   GO; GO:0031410; C:cytoplasmic vesicle; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR   GO; GO:0008333; P:endosome to lysosome transport; ISS:UniProtKB.
DR   GO; GO:0030163; P:protein catabolic process; ISS:UniProtKB.
DR   GO; GO:0032483; P:regulation of Rab protein signal transduction; IBA:GO_Central.
DR   FunFam; 3.40.50.11500:FF:000008; DENN domain containing 3; 1.
DR   FunFam; 3.30.450.200:FF:000008; DENN domain-containing protein 3; 1.
DR   FunFam; 2.130.10.10:FF:003343; DENN/MADD domain-containing 3a; 1.
DR   Gene3D; 3.30.450.200; -; 1.
DR   Gene3D; 3.40.50.11500; -; 1.
DR   Gene3D; 2.130.10.10; YVTN repeat-like/Quinoprotein amine dehydrogenase; 1.
DR   InterPro; IPR001194; cDENN_dom.
DR   InterPro; IPR005112; dDENN_dom.
DR   InterPro; IPR043153; DENN_C.
DR   InterPro; IPR051696; DENN_Domain_GEFs.
DR   InterPro; IPR057977; TPR_DENND3.
DR   InterPro; IPR037516; Tripartite_DENN.
DR   InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf.
DR   InterPro; IPR036322; WD40_repeat_dom_sf.
DR   InterPro; IPR001680; WD40_rpt.
DR   PANTHER; PTHR12296:SF21; DENN DOMAIN-CONTAINING PROTEIN 3; 1.
DR   PANTHER; PTHR12296; DENN DOMAIN-CONTAINING PROTEIN 4; 1.
DR   Pfam; PF02141; DENN; 1.
DR   Pfam; PF25570; TPR_DENND3; 1.
DR   Pfam; PF00400; WD40; 1.
DR   SMART; SM00801; dDENN; 1.
DR   SMART; SM00799; DENN; 1.
DR   SUPFAM; SSF50978; WD40 repeat-like; 1.
DR   PROSITE; PS50211; DENN; 1.
DR   PROSITE; PS00678; WD_REPEATS_1; 1.
DR   PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cytoplasm; Guanine-nucleotide releasing factor;
KW   Phosphoprotein; Proteomics identification; Reference proteome; Repeat;
KW   WD repeat.
FT   CHAIN           1..1198
FT                   /note="DENN domain-containing protein 3"
FT                   /id="PRO_0000304672"
FT   DOMAIN          1..163
FT                   /note="uDENN"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00304"
FT   DOMAIN          186..318
FT                   /note="cDENN"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00304"
FT   DOMAIN          320..424
FT                   /note="dDENN"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00304"
FT   REPEAT          893..931
FT                   /note="WD 1"
FT                   /evidence="ECO:0000255"
FT   REPEAT          937..973
FT                   /note="WD 2"
FT                   /evidence="ECO:0000255"
FT   REPEAT          977..1018
FT                   /note="WD 3"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1022..1059
FT                   /note="WD 4"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1065..1105
FT                   /note="WD 5"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1110..1152
FT                   /note="WD 6"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1158..1197
FT                   /note="WD 7"
FT                   /evidence="ECO:0000255"
FT   REGION          1..28
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          438..888
FT                   /note="Linker"
FT                   /evidence="ECO:0000305"
FT   COMPBIAS        1..10
FT                   /note="Basic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         472
FT                   /note="Phosphoserine; by ULK1"
FT                   /evidence="ECO:0000250|UniProtKB:A2RT67"
FT   MOD_RES         490
FT                   /note="Phosphoserine; by ULK1"
FT                   /evidence="ECO:0000250|UniProtKB:A2RT67"
FT   MOD_RES         858
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:A2RT67"
FT   VAR_SEQ         1..950
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_028075"
FT   VAR_SEQ         128
FT                   /note="C -> W (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_028077"
FT   VAR_SEQ         129..1198
FT                   /note="Missing (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_028078"
FT   VAR_SEQ         319..370
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_028080"
FT   VAR_SEQ         1133..1198
FT                   /note="VWVGSRGLGQGTPKGKIYVIDAERKTVEKELVAHMDTVRTLCSAEDRYVLSG
FT                   SGREEGKVAIWKGE -> VGWRARHPQHPRQVSLALAASPCSREPAARPRALLPSPLRV
FT                   PLLTGTCRVGANGPTGHHVLVSWCGPSTPQRIPPNWMASNDRT (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_028081"
FT   VARIANT         143
FT                   /note="S -> N (in dbSNP:rs307761)"
FT                   /id="VAR_035053"
FT   VARIANT         364
FT                   /note="Q -> R (in dbSNP:rs11997191)"
FT                   /id="VAR_035054"
SQ   SEQUENCE   1198 AA;  135890 MW;  52D51635DDD88A4E CRC64;
     MRSLRKKREK PRPEQWKGLP GPPRAPEPED VAVPGGVDLL TLPQLCFPGG VCVATEPKED
     CVHFLVLTDV CGNRTYGVVA QYYRPLHDEY CFYNGKTHRE CPGCFVPFAV CVVSRFPYYN
     SLKDCLSCLL ALLKPCKDFE VDSHIKDFAA KLSLIPSPPP GPLHLVFNMK SLQIVLPARA
     DPESPILDLD LHLPLLCFRP EKVLQILTCI LTEQRIVFFS SDWALLTLVT ECFMAYLYPL
     QWQHPFVPIL SDQMLDFVMA PTSFLMGCHL DHFEEVSKEA DGLVLINIDH GSITYSKSTD
     DNVDIPDVPL LAAQTFIQRV QSLQLHHELH AAHLLSSTDL KEGRAHRRSW QQKLNCQIQQ
     TTLQLLVSIF RDVKNHLNYE HRVFNSEEFL KTRAPGDHQF YKQVLDTYMF HSFLKARLNR
     RMDAFAQMDL DTQSEEDRIN GMLLSPRRPT VEKRASRKSS HLHVTHRRMV VSMPNLQDIA
     MPELAPRNSS LRLTDTAGCR GSSAVLNVTP KSPYTFKIPE IHFPLESKCV QAYHAHFVSM
     LSEAMCFLAP DNSLLLARYL YLRGLVYLMQ GQLLNALLDF QNLYKTDIRI FPTDLVKRTV
     ESMSAPEWEG AEQAPELMRL ISEILDKPHE ASKLDDHVKK FKLPKKHMQL GDFMKRVQES
     GIVKDASIIH RLFEALTVGQ EKQIDPETFK DFYNCWKETE AEAQEVSLPW LVMEHLDKNE
     CVCKLSSSVK TNLGVGKIAM TQKRLFLLTE GRPGYLEIST FRNIEEVRRT TTTFLLRRIP
     TLKIRVASKK EVFEANLKTE CDLWHLMVKE MWAGKKLADD HKDPHYVQQA LTNVLLMDAV
     VGTLQSPGAI YAASKLSYFD KMSNEMPMTL PETTLETLKH KINPSAGEAF PQAVDVLLYT
     PGHLDPAEKV EDAHPKLWCA LSEGKVTVFN ASSWTIHQHS FKVGTAKVNC MVMADQNQVW
     VGSEDSVIYI INVHSMSCNK QLTAHCSSVT DLIVQDGQEA PSNVYSCSMD GMVLVWNVST
     LQVTSRFQLP RGGLTSIRLH GGRLWCCTGN SIMVMKMNGS LHQELKIEEN FKDTSTSFLA
     FQLLPEEEQL WAACAGRSEV YIWSLKDLAQ PPQRVPLEDC SEINCMIRVK KQVWVGSRGL
     GQGTPKGKIY VIDAERKTVE KELVAHMDTV RTLCSAEDRY VLSGSGREEG KVAIWKGE
//