ID RHDF2_HUMAN Reviewed; 856 AA. AC Q6PJF5; A6NEM3; A8K801; Q5U607; Q5YGQ8; Q9H6E9; DT 01-JUL-2008, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-2008, sequence version 2. DT 08-MAY-2019, entry version 126. DE RecName: Full=Inactive rhomboid protein 2; DE Short=iRhom2; DE AltName: Full=Rhomboid 5 homolog 2; DE AltName: Full=Rhomboid family member 2; DE AltName: Full=Rhomboid veinlet-like protein 5; DE AltName: Full=Rhomboid veinlet-like protein 6; GN Name=RHBDF2; Synonyms=IRHOM2, RHBDL5, RHBDL6; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANT LEU-208. RC TISSUE=Liver; RA Kong X., Teng X., Hu L.; RT "Molecular cloning of human RHBDL5."; RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT RP LEU-208. RC TISSUE=Kidney epithelium, Spleen, and Synovium; 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16625196; DOI=10.1038/nature04689; RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.; RT "DNA sequence of human chromosome 17 and analysis of rearrangement in RT the human lineage."; RL Nature 440:1045-1049(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT RP LEU-208. RC TISSUE=Eye, and Uterus; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-90; SER-325 AND SER-328, RP AND IDENTIFICATION BY 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 [6] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., RA Blagoev B.; RT "System-wide temporal characterization of the proteome and RT phosphoproteome of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [7] RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND VARIANTS TOC THR-186 AND RP LEU-189. RX PubMed=22265016; DOI=10.1016/j.ajhg.2011.12.008; RA Blaydon D.C., Etheridge S.L., Risk J.M., Hennies H.C., Gay L.J., RA Carroll R., Plagnol V., McRonald F.E., Stevens H.P., Spurr N.K., RA Bishop D.T., Ellis A., Jankowski J., Field J.K., Leigh I.M., RA South A.P., Kelsell D.P.; RT "RHBDF2 mutations are associated with tylosis, a familial esophageal RT cancer syndrome."; RL Am. J. Hum. Genet. 90:340-346(2012). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-90; SER-113; SER-325 AND RP SER-328, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP 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 [9] 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., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [10] RP INTERACTION WITH ADAM17 AND FRMD8, AND SUBCELLULAR LOCATION. RX PubMed=29897333; DOI=10.7554/eLife.35032; RA Oikonomidi I., Burbridge E., Cavadas M., Sullivan G., Collis B., RA Naegele H., Clancy D., Brezinova J., Hu T., Bileck A., Gerner C., RA Bolado A., von Kriegsheim A., Martin S.J., Steinberg F., RA Strisovsky K., Adrain C.; RT "iTAP, a novel iRhom interactor, controls TNF secretion by policing RT the stability of iRhom/TACE."; RL Elife 7:0-0(2018). RN [11] RP INTERACTION WITH ADAM17 AND FRMD8. RX PubMed=29897336; DOI=10.7554/eLife.35012; RA Kuenzel U., Grieve A.G., Meng Y., Sieber B., Cowley S.A., Freeman M.; RT "FRMD8 promotes inflammatory and growth factor signalling by RT stabilising the iRhom/ADAM17 sheddase complex."; RL Elife 7:0-0(2018). CC -!- FUNCTION: Regulates ADAM17 protease, a sheddase of the epidermal CC growth factor (EGF) receptor ligands and TNF, thereby plays a role CC in sleep, cell survival, proliferation, migration and CC inflammation. Does not exhibit any protease activity on its own. CC {ECO:0000250|UniProtKB:Q80WQ6}. CC -!- SUBUNIT: Interacts with EGF (By similarity). Interacts (via CC cytoplasmic N-terminus) with FRMD8/iTAP; this interaction leads to CC mutual protein stabilization (PubMed:29897333, PubMed:29897336). CC Interacts with ADAM17/TACE (PubMed:29897333, PubMed:29897336). CC {ECO:0000250|UniProtKB:Q80WQ6, ECO:0000269|PubMed:29897333, CC ECO:0000269|PubMed:29897336}. CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000250|UniProtKB:Q80WQ6}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:Q80WQ6}. Cell membrane CC {ECO:0000269|PubMed:22265016, ECO:0000269|PubMed:29897333}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q6PJF5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q6PJF5-2; Sequence=VSP_034368; CC -!- TISSUE SPECIFICITY: Found in the epidermis and esophageal CC epithelium. {ECO:0000269|PubMed:22265016}. CC -!- DISEASE: Tylosis with esophageal cancer (TOC) [MIM:148500]: An CC autosomal dominant syndrome characterized by diffuse palmoplantar CC keratoderma, oral leukokeratosis, and a high lifetime risk of CC esophageal cancer. {ECO:0000269|PubMed:22265016}. Note=The disease CC is caused by mutations affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the peptidase S54 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH35829.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC Sequence=BAB15310.1; Type=Erroneous initiation; Note=Translation N-terminally extended.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY500247; AAS77567.1; -; mRNA. DR EMBL; AK025994; BAB15310.1; ALT_INIT; mRNA. DR EMBL; AK292135; BAF84824.1; -; mRNA. DR EMBL; AK292166; BAF84855.1; -; mRNA. DR EMBL; AC015802; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC035829; AAH35829.1; ALT_INIT; mRNA. DR EMBL; BC016034; AAH16034.2; -; mRNA. DR CCDS; CCDS32743.1; -. [Q6PJF5-1] DR CCDS; CCDS32744.1; -. [Q6PJF5-2] DR RefSeq; NP_001005498.2; NM_001005498.3. [Q6PJF5-2] DR RefSeq; NP_078875.4; NM_024599.5. [Q6PJF5-1] DR RefSeq; XP_005257726.1; XM_005257669.3. [Q6PJF5-1] DR RefSeq; XP_005257727.1; XM_005257670.1. [Q6PJF5-2] DR RefSeq; XP_011523551.1; XM_011525249.2. [Q6PJF5-2] DR RefSeq; XP_011523552.1; XM_011525250.2. [Q6PJF5-2] DR RefSeq; XP_011523553.1; XM_011525251.2. [Q6PJF5-2] DR RefSeq; XP_016880568.1; XM_017025079.1. [Q6PJF5-2] DR SMR; Q6PJF5; -. DR BioGrid; 122779; 11. DR ELM; Q6PJF5; -. DR STRING; 9606.ENSP00000322775; -. DR MEROPS; S54.953; -. DR iPTMnet; Q6PJF5; -. DR PhosphoSitePlus; Q6PJF5; -. DR BioMuta; RHBDF2; -. DR DMDM; 193806488; -. DR EPD; Q6PJF5; -. DR jPOST; Q6PJF5; -. DR MaxQB; Q6PJF5; -. DR PaxDb; Q6PJF5; -. DR PeptideAtlas; Q6PJF5; -. DR PRIDE; Q6PJF5; -. DR ProteomicsDB; 67199; -. DR ProteomicsDB; 67200; -. [Q6PJF5-2] DR Ensembl; ENST00000313080; ENSP00000322775; ENSG00000129667. [Q6PJF5-1] DR Ensembl; ENST00000591885; ENSP00000466867; ENSG00000129667. [Q6PJF5-2] DR GeneID; 79651; -. DR KEGG; hsa:79651; -. DR UCSC; uc002jrq.3; human. [Q6PJF5-1] DR CTD; 79651; -. DR DisGeNET; 79651; -. DR GeneCards; RHBDF2; -. DR HGNC; HGNC:20788; RHBDF2. DR HPA; HPA018080; -. DR MalaCards; RHBDF2; -. DR MIM; 148500; phenotype. DR MIM; 614404; gene. DR neXtProt; NX_Q6PJF5; -. DR OpenTargets; ENSG00000129667; -. DR Orphanet; 2198; Palmoplantar keratoderma-esophageal carcinoma syndrome. DR PharmGKB; PA134980674; -. DR eggNOG; KOG2290; Eukaryota. DR eggNOG; COG0705; LUCA. DR GeneTree; ENSGT00940000159027; -. DR HOGENOM; HOG000154118; -. DR InParanoid; Q6PJF5; -. DR OMA; VHCLDEV; -. DR OrthoDB; 1253228at2759; -. DR PhylomeDB; Q6PJF5; -. DR TreeFam; TF312988; -. DR ChiTaRS; RHBDF2; human. DR GeneWiki; RHBDF2; -. DR GenomeRNAi; 79651; -. DR PRO; PR:Q6PJF5; -. DR Proteomes; UP000005640; Chromosome 17. DR Bgee; ENSG00000129667; Expressed in 193 organ(s), highest expression level in small intestine Peyer's patch. DR ExpressionAtlas; Q6PJF5; baseline and differential. DR Genevisible; Q6PJF5; HS. DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB. DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0019838; F:growth factor binding; IEA:UniProtKB-KW. DR GO; GO:0050709; P:negative regulation of protein secretion; ISS:UniProtKB. DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW. DR GO; GO:0006508; P:proteolysis; IEA:InterPro. DR GO; GO:0042058; P:regulation of epidermal growth factor receptor signaling pathway; IBA:GO_Central. DR GO; GO:0050708; P:regulation of protein secretion; IBA:GO_Central. DR Gene3D; 1.20.1540.10; -; 1. DR InterPro; IPR022764; Peptidase_S54_rhomboid_dom. DR InterPro; IPR035952; Rhomboid-like_sf. DR InterPro; IPR022241; Rhomboid_SP. DR Pfam; PF01694; Rhomboid; 1. DR Pfam; PF12595; Rhomboid_SP; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Complete proteome; KW Disease mutation; Endoplasmic reticulum; Growth factor binding; KW Membrane; Palmoplantar keratoderma; Phosphoprotein; Polymorphism; KW Protein transport; Reference proteome; Transmembrane; KW Transmembrane helix; Transport. FT CHAIN 1 856 Inactive rhomboid protein 2. FT /FTId=PRO_0000341938. FT TOPO_DOM 1 409 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 410 430 Helical. {ECO:0000255}. FT TOPO_DOM 431 660 Lumenal. {ECO:0000255}. FT TRANSMEM 661 681 Helical. {ECO:0000255}. FT TOPO_DOM 682 692 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 693 713 Helical. {ECO:0000255}. FT TOPO_DOM 714 715 Lumenal. {ECO:0000255}. FT TRANSMEM 716 736 Helical. {ECO:0000255}. FT TOPO_DOM 737 747 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 748 768 Helical. {ECO:0000255}. FT TOPO_DOM 769 773 Lumenal. {ECO:0000255}. FT TRANSMEM 774 794 Helical. {ECO:0000255}. FT TOPO_DOM 795 802 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 803 823 Helical. {ECO:0000255}. FT TOPO_DOM 824 856 Lumenal. {ECO:0000255}. FT REGION 191 271 Involved in interaction with FRMD8. FT {ECO:0000269|PubMed:29897333}. FT MOD_RES 90 90 Phosphoserine. FT {ECO:0000244|PubMed:18669648, FT ECO:0000244|PubMed:23186163}. FT MOD_RES 113 113 Phosphoserine. FT {ECO:0000244|PubMed:23186163}. FT MOD_RES 117 117 Phosphoserine. FT {ECO:0000250|UniProtKB:Q80WQ6}. FT MOD_RES 323 323 Phosphoserine. FT {ECO:0000250|UniProtKB:Q80WQ6}. FT MOD_RES 325 325 Phosphoserine. FT {ECO:0000244|PubMed:18669648, FT ECO:0000244|PubMed:23186163}. FT MOD_RES 328 328 Phosphoserine. FT {ECO:0000244|PubMed:18669648, FT ECO:0000244|PubMed:23186163}. FT VAR_SEQ 51 79 Missing (in isoform 2). FT {ECO:0000303|PubMed:14702039, FT ECO:0000303|Ref.1}. FT /FTId=VSP_034368. FT VARIANT 186 186 I -> T (in TOC; dbSNP:rs387907129). FT {ECO:0000269|PubMed:22265016}. FT /FTId=VAR_067827. FT VARIANT 189 189 P -> L (in TOC; dbSNP:rs387907130). FT {ECO:0000269|PubMed:22265016}. FT /FTId=VAR_067828. FT VARIANT 208 208 P -> L (in dbSNP:rs3744045). FT {ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334, FT ECO:0000269|Ref.1}. FT /FTId=VAR_044125. FT VARIANT 249 249 A -> T (in dbSNP:rs34814954). FT /FTId=VAR_044126. FT VARIANT 528 528 D -> Y (in dbSNP:rs11553545). FT /FTId=VAR_044127. FT CONFLICT 67 67 A -> S (in Ref. 2; BAF84824 and 4; FT AAH16034). {ECO:0000305}. FT CONFLICT 705 705 N -> D (in Ref. 2; BAF84855). FT {ECO:0000305}. FT CONFLICT 852 852 D -> G (in Ref. 2; BAF84855). FT {ECO:0000305}. SQ SEQUENCE 856 AA; 96686 MW; 69C40A21EBDBDDC0 CRC64; MASADKNGGS VSSVSSSRLQ SRKPPNLSIT IPPPEKETQA PGEQDSMLPE GFQNRRLKKS QPRTWAAHTT ACPPSFLPKR KNPAYLKSVS LQEPRSRWQE SSEKRPGFRR QASLSQSIRK GAAQWFGVSG DWEGQRQQWQ RRSLHHCSMR YGRLKASCQR DLELPSQEAP SFQGTESPKP CKMPKIVDPL ARGRAFRHPE EMDRPHAPHP PLTPGVLSLT SFTSVRSGYS HLPRRKRMSV AHMSLQAAAA LLKGRSVLDA TGQRCRVVKR SFAFPSFLEE DVVDGADTFD SSFFSKEEMS SMPDDVFESP PLSASYFRGI PHSASPVSPD GVQIPLKEYG RAPVPGPRRG KRIASKVKHF AFDRKKRHYG LGVVGNWLNR SYRRSISSTV QRQLESFDSH RPYFTYWLTF VHVIITLLVI CTYGIAPVGF AQHVTTQLVL RNKGVYESVK YIQQENFWVG PSSIDLIHLG AKFSPCIRKD GQIEQLVLRE RDLERDSGCC VQNDHSGCIQ TQRKDCSETL ATFVKWQDDT GPPMDKSDLG QKRTSGAVCH QDPRTCEEPA SSGAHIWPDD ITKWPICTEQ ARSNHTGFLH MDCEIKGRPC CIGTKGSCEI TTREYCEFMH GYFHEEATLC SQVHCLDKVC GLLPFLNPEV PDQFYRLWLS LFLHAGVVHC LVSVVFQMTI LRDLEKLAGW HRIAIIFILS GITGNLASAI FLPYRAEVGP AGSQFGLLAC LFVELFQSWP LLERPWKAFL NLSAIVLFLF ICGLLPWIDN IAHIFGFLSG LLLAFAFLPY ITFGTSDKYR KRALILVSLL AFAGLFAALV LWLYIYPINW PWIEHLTCFP FTSRFCEKYE LDQVLH //