GREM2_HUMAN
ID GREM2_HUMAN Reviewed; 168 AA.
AC Q9H772; Q86UD9;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 143.
DE RecName: Full=Gremlin-2;
DE AltName: Full=Cysteine knot superfamily 1, BMP antagonist 2;
DE AltName: Full=DAN domain family member 3;
DE AltName: Full=Protein related to DAN and cerberus;
DE Flags: Precursor;
GN Name=GREM2; Synonyms=CKTSF1B2, DAND3, PRDC;
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].
RC TISSUE=Colon;
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=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 IDENTIFICATION.
RX PubMed=15254711;
RA Katoh M., Katoh M.;
RT "Identification and characterization of human CKTSF1B2 and CKTSF1B3 genes
RT in silico.";
RL Oncol. Rep. 12:423-427(2004).
RN [5]
RP VARIANTS STHAG9 VAL-13; GLU-76 AND ASP-136.
RX PubMed=26416033; DOI=10.1177/0022034515608168;
RA Kantaputra P.N., Kaewgahya M., Hatsadaloi A., Vogel P., Kawasaki K.,
RA Ohazama A., Ketudat Cairns J.R.;
RT "GREMLIN 2 mutations and dental anomalies.";
RL J. Dent. Res. 94:1646-1652(2015).
CC -!- FUNCTION: Cytokine that inhibits the activity of BMP2 and BMP4 in a
CC dose-dependent manner, and thereby modulates signaling by BMP family
CC members. Contributes to the regulation of embryonic morphogenesis via
CC BMP family members. Antagonizes BMP4-induced suppression of
CC progesterone production in granulosa cells.
CC {ECO:0000250|UniProtKB:O88273}.
CC -!- SUBUNIT: Homodimer. Interacts with BMP2, BMP4 and BMP7, but has lower
CC affinity for BMP7 than for BMP2 and BMP4. Binds heparin; this impairs
CC the interaction with BMP2. {ECO:0000250|UniProtKB:O88273}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:O88273}.
CC -!- DISEASE: Tooth agenesis, selective, 9 (STHAG9) [MIM:617275]: A form of
CC selective tooth agenesis, a common anomaly characterized by the
CC congenital absence of one or more teeth. Selective tooth agenesis
CC without associated systemic disorders has sometimes been divided into 2
CC types: oligodontia, defined as agenesis of 6 or more permanent teeth,
CC and hypodontia, defined as agenesis of less than 6 teeth. The number in
CC both cases does not include absence of third molars (wisdom teeth).
CC STHAG9 inheritance is autosomal dominant.
CC {ECO:0000269|PubMed:26416033}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the DAN family. {ECO:0000305}.
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DR EMBL; AK024848; BAB15026.1; -; mRNA.
DR EMBL; AL358176; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC046632; AAH46632.1; -; mRNA.
DR CCDS; CCDS31070.1; -.
DR RefSeq; NP_071914.3; NM_022469.3.
DR RefSeq; XP_011542551.1; XM_011544249.2.
DR AlphaFoldDB; Q9H772; -.
DR SMR; Q9H772; -.
DR BioGRID; 122150; 37.
DR STRING; 9606.ENSP00000318650; -.
DR GlyGen; Q9H772; 2 sites.
DR iPTMnet; Q9H772; -.
DR PhosphoSitePlus; Q9H772; -.
DR BioMuta; GREM2; -.
DR DMDM; 62510699; -.
DR jPOST; Q9H772; -.
DR MassIVE; Q9H772; -.
DR PaxDb; Q9H772; -.
DR PeptideAtlas; Q9H772; -.
DR PRIDE; Q9H772; -.
DR ProteomicsDB; 81084; -.
DR Antibodypedia; 4089; 164 antibodies from 29 providers.
DR DNASU; 64388; -.
DR Ensembl; ENST00000318160.5; ENSP00000318650.4; ENSG00000180875.5.
DR GeneID; 64388; -.
DR KEGG; hsa:64388; -.
DR MANE-Select; ENST00000318160.5; ENSP00000318650.4; NM_022469.4; NP_071914.3.
DR UCSC; uc001hys.4; human.
DR CTD; 64388; -.
DR DisGeNET; 64388; -.
DR GeneCards; GREM2; -.
DR HGNC; HGNC:17655; GREM2.
DR HPA; ENSG00000180875; Tissue enhanced (gallbladder, liver).
DR MalaCards; GREM2; -.
DR MIM; 608832; gene.
DR MIM; 617275; phenotype.
DR neXtProt; NX_Q9H772; -.
DR OpenTargets; ENSG00000180875; -.
DR PharmGKB; PA134968998; -.
DR VEuPathDB; HostDB:ENSG00000180875; -.
DR eggNOG; ENOG502QZFW; Eukaryota.
DR GeneTree; ENSGT00940000154209; -.
DR HOGENOM; CLU_101024_2_0_1; -.
DR InParanoid; Q9H772; -.
DR OMA; MIWKFAV; -.
DR OrthoDB; 1270652at2759; -.
DR PhylomeDB; Q9H772; -.
DR TreeFam; TF106445; -.
DR PathwayCommons; Q9H772; -.
DR Reactome; R-HSA-201451; Signaling by BMP.
DR SignaLink; Q9H772; -.
DR BioGRID-ORCS; 64388; 22 hits in 1071 CRISPR screens.
DR ChiTaRS; GREM2; human.
DR GenomeRNAi; 64388; -.
DR Pharos; Q9H772; Tbio.
DR PRO; PR:Q9H772; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q9H772; protein.
DR Bgee; ENSG00000180875; Expressed in gall bladder and 131 other tissues.
DR Genevisible; Q9H772; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0036122; F:BMP binding; IBA:GO_Central.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0008201; F:heparin binding; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0048018; F:receptor ligand activity; IBA:GO_Central.
DR GO; GO:0009887; P:animal organ morphogenesis; IBA:GO_Central.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0048263; P:determination of dorsal identity; IEA:Ensembl.
DR GO; GO:0010172; P:embryonic body morphogenesis; ISS:UniProtKB.
DR GO; GO:0060300; P:regulation of cytokine activity; ISS:UniProtKB.
DR GO; GO:0038098; P:sequestering of BMP from receptor via BMP binding; IBA:GO_Central.
DR Gene3D; 2.10.90.10; -; 1.
DR InterPro; IPR006207; Cys_knot_C.
DR InterPro; IPR029034; Cystine-knot_cytokine.
DR InterPro; IPR004133; DAN.
DR InterPro; IPR017159; Gremlin-1/2.
DR Pfam; PF03045; DAN; 1.
DR PIRSF; PIRSF037254; Gremlin_precursor; 1.
DR SMART; SM00041; CT; 1.
DR PROSITE; PS01225; CTCK_2; 1.
PE 1: Evidence at protein level;
KW Cytokine; Developmental protein; Disease variant; Disulfide bond;
KW Glycoprotein; Heparin-binding; Reference proteome; Secreted; Signal.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..168
FT /note="Gremlin-2"
FT /id="PRO_0000006720"
FT DOMAIN 73..163
FT /note="CTCK"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00039"
FT CARBOHYD 40
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 161
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 73..123
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00039"
FT DISULFID 87..137
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00039"
FT DISULFID 97..155
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00039"
FT DISULFID 101..157
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00039"
FT VARIANT 13
FT /note="A -> V (in STHAG9; dbSNP:rs373941682)"
FT /evidence="ECO:0000269|PubMed:26416033"
FT /id="VAR_078067"
FT VARIANT 76
FT /note="Q -> E (in STHAG9; dbSNP:rs142343894)"
FT /evidence="ECO:0000269|PubMed:26416033"
FT /id="VAR_078068"
FT VARIANT 131
FT /note="V -> I (in dbSNP:rs34188522)"
FT /id="VAR_048876"
FT VARIANT 136
FT /note="E -> D (in STHAG9; dbSNP:rs1057519288)"
FT /evidence="ECO:0000269|PubMed:26416033"
FT /id="VAR_078069"
FT CONFLICT 11
FT /note="L -> M (in Ref. 3; AAH46632)"
FT /evidence="ECO:0000305"
FT CONFLICT 31
FT /note="P -> H (in Ref. 3; AAH46632)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 168 AA; 19320 MW; D5A4E4E818BF8C0E CRC64;
MFWKLSLSLF LVAVLVKVAE ARKNRPAGAI PSPYKDGSSN NSERWQHQIK EVLASSQEAL
VVTERKYLKS DWCKTQPLRQ TVSEEGCRSR TILNRFCYGQ CNSFYIPRHV KKEEESFQSC
AFCKPQRVTS VLVELECPGL DPPFRLKKIQ KVKQCRCMSV NLSDSDKQ
