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 24-JAN-2024, entry version 135.
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 intereferes with this interaction leading to
CC an open conformation and enhances the GEF activity of the protein
CC towards 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_055772.2; NM_014957.2.
DR AlphaFoldDB; A2RUS2; -.
DR SMR; A2RUS2; -.
DR BioGRID; 116562; 6.
DR IntAct; A2RUS2; 8.
DR STRING; 9606.ENSP00000428714; -.
DR GlyCosmos; A2RUS2; 2 sites, 1 glycan.
DR GlyGen; A2RUS2; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; A2RUS2; -.
DR PhosphoSitePlus; A2RUS2; -.
DR BioMuta; DENND3; -.
DR EPD; A2RUS2; -.
DR jPOST; A2RUS2; -.
DR MassIVE; A2RUS2; -.
DR MaxQB; A2RUS2; -.
DR PaxDb; 9606-ENSP00000262585; -.
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; 53 antibodies from 16 providers.
DR DNASU; 22898; -.
DR Ensembl; ENST00000262585.6; ENSP00000262585.2; ENSG00000105339.11. [A2RUS2-1]
DR Ensembl; ENST00000424248.2; ENSP00000410594.1; ENSG00000105339.11. [A2RUS2-2]
DR GeneID; 22898; -.
DR KEGG; hsa:22898; -.
DR UCSC; uc003yvy.4; human. [A2RUS2-1]
DR AGR; HGNC:29134; -.
DR CTD; 22898; -.
DR DisGeNET; 22898; -.
DR GeneCards; DENND3; -.
DR HGNC; HGNC:29134; DENND3.
DR HPA; ENSG00000105339; Tissue enhanced (bone).
DR MIM; 617503; gene.
DR neXtProt; NX_A2RUS2; -.
DR OpenTargets; ENSG00000105339; -.
DR PharmGKB; PA142671987; -.
DR VEuPathDB; HostDB:ENSG00000105339; -.
DR eggNOG; KOG2127; Eukaryota.
DR GeneTree; ENSGT00940000155784; -.
DR HOGENOM; CLU_280008_0_0_1; -.
DR InParanoid; A2RUS2; -.
DR OrthoDB; 5354449at2759; -.
DR PhylomeDB; A2RUS2; -.
DR TreeFam; TF331814; -.
DR PathwayCommons; A2RUS2; -.
DR Reactome; R-HSA-8876198; RAB GEFs exchange GTP for GDP on RABs.
DR SignaLink; A2RUS2; -.
DR SIGNOR; A2RUS2; -.
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 Genevisible; A2RUS2; HS.
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 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; IPR037516; Tripartite_DENN.
DR InterPro; IPR005113; uDENN_dom.
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; PF03456; uDENN; 1.
DR Pfam; PF00400; WD40; 1.
DR SMART; SM00801; dDENN; 1.
DR SMART; SM00799; DENN; 1.
DR SMART; SM00320; WD40; 3.
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; Reference proteome; Repeat; 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 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
//
