RFFL_MOUSE
ID RFFL_MOUSE Reviewed; 377 AA.
AC Q6ZQM0; Q5SVC2; Q5SVC4; Q9D543; Q9D9B1;
DT 27-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 143.
DE RecName: Full=E3 ubiquitin-protein ligase rififylin {ECO:0000305};
DE EC=2.3.2.27 {ECO:0000250|UniProtKB:Q8WZ73};
DE AltName: Full=RING finger and FYVE-like domain-containing protein 1;
DE Short=Fring {ECO:0000312|EMBL:AAL30769.1};
DE AltName: Full=RING-type E3 ubiquitin transferase rififylin {ECO:0000305};
GN Name=Rffl {ECO:0000312|MGI:MGI:1914588};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC STRAIN=C57BL/6J;
RA Hong W.;
RT "Fring, a protein with a modified FYVE domain and a RING domain.";
RL Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2; 3 AND 4).
RC STRAIN=C57BL/6J; TISSUE=Testis;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (ISOFORMS 2 AND 3).
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP FUNCTION IN ENDOCYTIC RECYCLING, SUBCELLULAR LOCATION, DOMAIN, AND TISSUE
RP SPECIFICITY.
RX PubMed=15229288; DOI=10.1091/mbc.e04-04-0274;
RA Coumailleau F., Das V., Alcover A., Raposo G., Vandormael-Pournin S.,
RA Le Bras S., Baldacci P., Dautry-Varsat A., Babinet C., Cohen-Tannoudji M.;
RT "Over-expression of Rififylin, a new RING finger and FYVE-like domain-
RT containing protein, inhibits recycling from the endocytic recycling
RT compartment.";
RL Mol. Biol. Cell 15:4444-4456(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=19138581; DOI=10.1016/j.cub.2008.11.040;
RA Ahmed A.U., Moulin M., Coumailleau F., Wong W.W., Miasari M., Carter H.,
RA Silke J., Cohen-Tannoudji M., Vince J.E., Vaux D.L.;
RT "CARP2 deficiency does not alter induction of NF-kappaB by TNFalpha.";
RL Curr. Biol. 19:R15-R17(2009).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-240; SER-243; SER-246 AND
RP SER-254, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas, Spleen,
RC and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [8]
RP FUNCTION IN CELL MIGRATION, AND INDUCTION BY LPA.
RX PubMed=22609986; DOI=10.1038/ncb2507;
RA Gan X., Wang J., Wang C., Sommer E., Kozasa T., Srinivasula S., Alessi D.,
RA Offermanns S., Simon M.I., Wu D.;
RT "PRR5L degradation promotes mTORC2-mediated PKC-delta phosphorylation and
RT cell migration downstream of Galpha12.";
RL Nat. Cell Biol. 14:686-696(2012).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that regulates several biological
CC processes through the ubiquitin-mediated proteasomal degradation of
CC various target proteins. Mediates 'Lys-48'-linked polyubiquitination of
CC PRR5L and its subsequent proteasomal degradation thereby indirectly
CC regulating cell migration through the mTORC2 complex. Also
CC ubiquitinates the caspases CASP8 and CASP10, promoting their
CC proteasomal degradation, to negatively regulate apoptosis downstream of
CC death domain receptors. Also negatively regulates the tumor necrosis
CC factor-mediated signaling pathway through targeting of RIPK1 to
CC ubiquitin-mediated proteasomal degradation. Negatively regulates
CC p53/TP53 through its direct ubiquitination and targeting to proteasomal
CC degradation. Indirectly, may also negatively regulate p53/TP53 through
CC ubiquitination and degradation of SFN. May also play a role in
CC endocytic recycling. {ECO:0000269|PubMed:15229288,
CC ECO:0000269|PubMed:22609986}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000250|UniProtKB:Q8WZ73};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000250|UniProtKB:Q8WZ73}.
CC -!- SUBUNIT: Interacts with CASP8 and CASP10. Interacts with RIPK1 (via
CC protein kinase domain); involved in RIPK1 ubiquitination. Interacts
CC with PRR5L. Interacts (via RING-type zinc finger) with p53/TP53;
CC involved in p53/TP53 ubiquitination. Interacts (via RING-type zinc
CC finger) with MDM2; the interaction stabilizes MDM2.
CC {ECO:0000250|UniProtKB:Q8WZ73}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:15229288}.
CC Cell membrane {ECO:0000269|PubMed:15229288}; Peripheral membrane
CC protein {ECO:0000269|PubMed:15229288}. Recycling endosome membrane
CC {ECO:0000305|PubMed:15229288}; Peripheral membrane protein
CC {ECO:0000305|PubMed:15229288}. Note=The FYVE-type zinc finger may
CC mediate phosphatidylinositol phosphate-binding and control subcellular
CC localization.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q6ZQM0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6ZQM0-2; Sequence=VSP_015753;
CC Name=3;
CC IsoId=Q6ZQM0-3; Sequence=VSP_015753, VSP_015754;
CC Name=4;
CC IsoId=Q6ZQM0-4; Sequence=VSP_015753, VSP_015754, VSP_015755,
CC VSP_015756;
CC -!- TISSUE SPECIFICITY: Ubiquitous. Detected in heart, brain, spleen, lung,
CC liver, skeletal muscle, kidney, testis, thymus, whole embryo and
CC embryonic stem cells. {ECO:0000269|PubMed:15229288}.
CC -!- INDUCTION: Up-regulation by LPA/lysophosphatidic acid is dependent on
CC GNA12. {ECO:0000269|PubMed:22609986}.
CC -!- DOMAIN: The FYVE-type zinc finger domain is required for localization
CC to the recycling endosome membranes and the function in endocytic
CC recycling. {ECO:0000269|PubMed:15229288}.
CC -!- DOMAIN: The RING-type zinc finger is required for the ubiquitination of
CC target proteins. {ECO:0000250|UniProtKB:Q8WZ73}.
CC -!- PTM: Autoubiquitinated. {ECO:0000250}.
CC -!- PTM: Palmitoylated. {ECO:0000250}.
CC -!- PTM: Undergoes caspase-mediated cleavage upon death-receptor
CC activation, by TNFSF10 for instance. May be mediated by the caspases
CC CASP8 and CASP10 in a negative feedback loop (By similarity).
CC {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype.
CC {ECO:0000269|PubMed:19138581}.
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DR EMBL; AF434814; AAL30769.1; -; mRNA.
DR EMBL; AK007189; BAB24891.1; -; mRNA.
DR EMBL; AK015806; BAB29984.1; -; mRNA.
DR EMBL; AK028095; BAC25744.1; -; mRNA.
DR EMBL; AK128983; BAC87665.1; -; mRNA.
DR EMBL; AL645594; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS25148.1; -. [Q6ZQM0-2]
DR CCDS; CCDS25149.1; -. [Q6ZQM0-3]
DR CCDS; CCDS48867.1; -. [Q6ZQM0-1]
DR RefSeq; NP_001158042.1; NM_001164570.1. [Q6ZQM0-1]
DR RefSeq; NP_080373.1; NM_026097.3. [Q6ZQM0-3]
DR AlphaFoldDB; Q6ZQM0; -.
DR SMR; Q6ZQM0; -.
DR STRING; 10090.ENSMUSP00000021036; -.
DR iPTMnet; Q6ZQM0; -.
DR PhosphoSitePlus; Q6ZQM0; -.
DR SwissPalm; Q6ZQM0; -.
DR jPOST; Q6ZQM0; -.
DR MaxQB; Q6ZQM0; -.
DR PaxDb; Q6ZQM0; -.
DR PRIDE; Q6ZQM0; -.
DR ProteomicsDB; 253228; -. [Q6ZQM0-1]
DR ProteomicsDB; 253229; -. [Q6ZQM0-2]
DR ProteomicsDB; 253230; -. [Q6ZQM0-3]
DR ProteomicsDB; 253231; -. [Q6ZQM0-4]
DR TopDownProteomics; Q6ZQM0-2; -. [Q6ZQM0-2]
DR Antibodypedia; 3764; 263 antibodies from 29 providers.
DR DNASU; 67338; -.
DR Ensembl; ENSMUST00000021036; ENSMUSP00000021036; ENSMUSG00000020696. [Q6ZQM0-3]
DR Ensembl; ENSMUST00000074515; ENSMUSP00000074108; ENSMUSG00000020696. [Q6ZQM0-2]
DR Ensembl; ENSMUST00000093975; ENSMUSP00000091510; ENSMUSG00000020696. [Q6ZQM0-1]
DR Ensembl; ENSMUST00000103218; ENSMUSP00000099507; ENSMUSG00000020696. [Q6ZQM0-4]
DR Ensembl; ENSMUST00000108173; ENSMUSP00000103808; ENSMUSG00000020696. [Q6ZQM0-2]
DR GeneID; 67338; -.
DR KEGG; mmu:67338; -.
DR UCSC; uc007kni.2; mouse. [Q6ZQM0-1]
DR CTD; 117584; -.
DR MGI; MGI:1914588; Rffl.
DR VEuPathDB; HostDB:ENSMUSG00000020696; -.
DR eggNOG; KOG4275; Eukaryota.
DR GeneTree; ENSGT00390000012719; -.
DR HOGENOM; CLU_041431_1_0_1; -.
DR InParanoid; Q6ZQM0; -.
DR OMA; EMCREKD; -.
DR TreeFam; TF325195; -.
DR Reactome; R-MMU-6804757; Regulation of TP53 Degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 67338; 7 hits in 73 CRISPR screens.
DR ChiTaRS; Rffl; mouse.
DR PRO; PR:Q6ZQM0; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q6ZQM0; protein.
DR Bgee; ENSMUSG00000020696; Expressed in floor plate of midbrain and 246 other tissues.
DR ExpressionAtlas; Q6ZQM0; baseline and differential.
DR Genevisible; Q6ZQM0; MM.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:MGI.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0010008; C:endosome membrane; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0055038; C:recycling endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0002039; F:p53 binding; ISO:MGI.
DR GO; GO:0002020; F:protease binding; ISO:MGI.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; ISS:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0006886; P:intracellular protein transport; IDA:MGI.
DR GO; GO:2001271; P:negative regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis; ISS:UniProtKB.
DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; ISS:UniProtKB.
DR GO; GO:1901797; P:negative regulation of signal transduction by p53 class mediator; ISS:UniProtKB.
DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0010762; P:regulation of fibroblast migration; IMP:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR036361; SAP_dom_sf.
DR InterPro; IPR011011; Znf_FYVE_PHD.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR SMART; SM00184; RING; 1.
DR SUPFAM; SSF57903; SSF57903; 1.
DR SUPFAM; SSF68906; SSF68906; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Apoptosis; Cell membrane; Cytoplasm; Endosome;
KW Lipoprotein; Membrane; Metal-binding; Palmitate; Phosphoprotein;
KW Reference proteome; Repeat; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..377
FT /note="E3 ubiquitin-protein ligase rififylin"
FT /id="PRO_0000056026"
FT DOMAIN 115..134
FT /note="SAP 1"
FT DOMAIN 264..278
FT /note="SAP 2"
FT ZN_FING 55..107
FT /note="FYVE-type"
FT ZN_FING 330..365
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 176..249
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 193..216
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 240
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 243
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 246
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 254
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT VAR_SEQ 1..14
FT /note="Missing (in isoform 2, isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:16141072, ECO:0000303|Ref.1"
FT /id="VSP_015753"
FT VAR_SEQ 211..238
FT /note="Missing (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:16141072, ECO:0000303|Ref.1"
FT /id="VSP_015754"
FT VAR_SEQ 318..335
FT /note="GGAVPSGLEENLCKICMD -> ASHLLWEVFFDLMFHSYV (in isoform
FT 4)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_015755"
FT VAR_SEQ 336..377
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_015756"
FT CONFLICT 52
FT /note="P -> L (in Ref. 2; BAB29984)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 377 AA; 42249 MW; B0E9E87D446902D1 CRC64;
MSQPSLWKDS HYFIMWASCC NWFCLDGQPE EAPPPQGART QAYSNPGYSS FPSPTGSEPS
CKACGVHFAS TTRKQTCLDC KKNFCMTCSS QEGNGPRLCL LCLRFRATAF QREELMKMKV
KDLRDYLSLH DISTEMCREK EELVFLVLGQ QPVISEADRT RVPHLPQAFP EQQAFLTQPQ
TSTVPPTSPG LPSSPAQVTS VPLAQDQETQ QAVGHVSQDH EEPIFPESTA RVPTEDETQS
VDSEDSFVPG RRASLSDLTH LEDIEGLTVR QLKEILARNF VNYKGCCEKW ELMERVTRLY
KDQKGLQHLV SGNEDQNGGA VPSGLEENLC KICMDSPIDC VLLECGHMVT CTKCGKRMNE
CPICRQYVIR AVHVFRS
