ID CILP1_HUMAN Reviewed; 1184 AA. AC O75339; B2R8F7; Q6UW99; Q8IYI5; DT 05-JUL-2005, integrated into UniProtKB/Swiss-Prot. DT 11-JAN-2011, sequence version 4. DT 14-DEC-2011, entry version 91. DE RecName: Full=Cartilage intermediate layer protein 1; DE Short=CILP-1; DE AltName: Full=Cartilage intermediate-layer protein; DE Contains: DE RecName: Full=Cartilage intermediate layer protein 1 C1; DE Contains: DE RecName: Full=Cartilage intermediate layer protein 1 C2; DE Flags: Precursor; GN Name=CILP; ORFNames=UNQ602/PRO1188; 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], PROTEIN SEQUENCE OF 39-58; 282-291; RP 301-317; 332-338; 341-356; 361-365; 524-547; 575-594; 680-690 AND RP 698-707, GLYCOSYLATION AT ASN-346, PROTEOLYTIC PROCESSING, TISSUE RP SPECIFICITY, AND VARIANTS LEU-59; THR-395; GLU-575; ARG-979 AND RP SER-1166. RC TISSUE=Articular cartilage; RX MEDLINE=98389785; PubMed=9722584; DOI=10.1074/jbc.273.36.23469; RA Lorenzo P., Neame P., Sommarin Y., Heinegaerd D.; RT "Cloning and deduced amino acid sequence of a novel cartilage protein RT (CILP) identifies a proform including a nucleotide RT pyrophosphohydrolase."; RL J. Biol. Chem. 273:23469-23475(1998). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-59; PHE-327; RP THR-395; GLU-575; VAL-895; ARG-979; ASN-1101; SER-1166 AND ALA-1168. RX MEDLINE=99253146; PubMed=10319588; DOI=10.1007/s100380050143; RA Nakamura I., Okawa A., Ikegawa S., Takaoka K., Nakamura Y.; RT "Genomic organization, mapping, and polymorphisms of the gene encoding RT human cartilage intermediate layer protein (CILP)."; RL J. Hum. Genet. 44:203-205(1999). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-59; THR-395; RP GLU-575; ARG-979 AND SER-1166. RX MEDLINE=20068039; PubMed=10601732; DOI=10.1016/S0945-053X(99)00035-9; RA Lorenzo P., Aman P., Sommarin Y., Heinegaerd D.; RT "The human CILP gene: exon/intron organization and chromosomal RT mapping."; RL Matrix Biol. 18:445-454(1999). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS THR-395; GLU-575 RP AND ARG-979. RX MEDLINE=22887296; PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., RA Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale RT effort to identify novel human secreted and transmembrane proteins: a RT bioinformatics assessment."; RL Genome Res. 13:2265-2270(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS THR-395; GLU-575; RP ARG-979 AND SER-1166. RC TISSUE=Testis; 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16572171; DOI=10.1038/nature04601; RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S., RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., RA Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., RA Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., RA Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., RA Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., RA Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., RA Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., RA Nusbaum C.; RT "Analysis of the DNA sequence and duplication history of human RT chromosome 15."; RL Nature 440:671-675(2006). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS GLU-575; ARG-979 RP AND SER-1166. RC TISSUE=Ovary; 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 [8] RP SUBUNIT, GLYCOSYLATION, AND TISSUE SPECIFICITY. RX MEDLINE=98389784; PubMed=9722583; DOI=10.1074/jbc.273.36.23463; RA Lorenzo P., Bayliss M.T., Heinegaerd D.; RT "A novel cartilage protein (CILP) present in the mid-zone of human RT articular cartilage increases with age."; RL J. Biol. Chem. 273:23463-23468(1998). RN [9] RP TISSUE SPECIFICITY. RX MEDLINE=22370301; PubMed=12483726; DOI=10.1002/art.10632; RA Hirose J., Ryan L.M., Masuda I.; RT "Up-regulated expression of cartilage intermediate-layer protein and RT ANK in articular hyaline cartilage from patients with calcium RT pyrophosphate dihydrate crystal deposition disease."; RL Arthritis Rheum. 46:3218-3229(2002). RN [10] RP INVOLVEMENT IN OSTEOARTHRITIS AND RHEUMATOID ARTHRITIS. RX MEDLINE=21212516; PubMed=11315923; RX DOI=10.1002/1529-0131(200104)44:4<838::AID-ANR140>3.0.CO;2-C; RA Tsuruha J., Masuko-Hongo K., Kato T., Sakata M., Nakamura H., RA Nishioka K.; RT "Implication of cartilage intermediate layer protein in cartilage RT destruction in subsets of patients with osteoarthritis and rheumatoid RT arthritis."; RL Arthritis Rheum. 44:838-845(2001). RN [11] RP FUNCTION. RX MEDLINE=22630078; PubMed=12746903; DOI=10.1002/art.10927; RA Johnson K., Farley D., Hu S.-I., Terkeltaub R.; RT "One of two chondrocyte-expressed isoforms of cartilage intermediate- RT layer protein functions as an insulin-like growth factor 1 RT antagonist."; RL Arthritis Rheum. 48:1302-1314(2003). RN [12] RP IMMUNISATION. RX PubMed=14962958; DOI=10.1136/ard.2003.008045; RA Yao Z., Nakamura H., Masuko-Hongo K., Suzuki-Kurokawa M., Nishioka K., RA Kato T.; RT "Characterisation of cartilage intermediate layer protein (CILP)- RT induced arthropathy in mice."; RL Ann. Rheum. Dis. 63:252-258(2004). RN [13] RP INVOLVEMENT IN OSTEOARTHRITIS. RX PubMed=15378262; DOI=10.1007/s00296-004-0497-2; RA Du H., Masuko-Hongo K., Nakamura H., Xiang Y., Bao C.-D., Wang X.-D., RA Chen S.-L., Nishioka K., Kato T.; RT "The prevalence of autoantibodies against cartilage intermediate layer RT protein, YKL-39, osteopontin, and cyclic citrullinated peptide in RT patients with early-stage knee osteoarthritis: evidence of a variety RT of autoimmune processes."; RL Rheumatol. Int. 26:35-41(2005). RN [14] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INTERACTION WITH RP TGFB1, AND ASSOCIATION OF VARIANT THR-395 WITH SUSCEPTIBILITY TO RP INTERVERTEBRAL DISK DISEASE. RX PubMed=15864306; DOI=10.1038/ng1557; RA Seki S., Kawaguchi Y., Chiba K., Mikami Y., Kizawa H., Oya T., Mio F., RA Mori M., Miyamoto Y., Masuda I., Tsunoda T., Kamata M., Kubo T., RA Toyama Y., Kimura T., Nakamura Y., Ikegawa S.; RT "A functional SNP in CILP, encoding cartilage intermediate layer RT protein, is associated with susceptibility to lumbar disc disease."; RL Nat. Genet. 37:607-612(2005). CC -!- FUNCTION: Probably plays a role in cartilage scaffolding. May act CC by antagonizing TGF-beta1 (TGFB1) and IGF1 functions. Has the CC ability to suppress IGF1-induced proliferation and sulfated CC proteoglycan synthesis, and inhibits ligand-induced IGF1R CC autophosphorylation. May inhibit TGFB1-mediated induction of CC cartilage matrix genes via its interaction with TGFB1. CC Overexpression may lead to impair chondrocyte growth and matrix CC repair and indirectly promote inorganic pyrophosphate (PPi) CC supersaturation in aging and osteoarthritis cartilage. CC -!- SUBUNIT: Monomer. Interacts with TGFB1. CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular CC matrix. CC -!- TISSUE SPECIFICITY: Specifically expressed in cartilage. Localizes CC in the intermediates layer of articular cartilage but neither in CC the superficial nor in the deepest regions. Specifically and CC highly expressed in intervertebral disk tissue. Expression CC increases with aging in hip articular cartilage. Overexpressed in CC articular hyaline cartilage from patients with calcium CC pyrophosphate dihydrate crystal deposition disease (CPPD). CC Expression in intervertebral disk tissue from individuals with CC lumbar disk disease increases as disk degeneration progresses. CC -!- PTM: Cleaved into 2 chains possibly by a furin-like protease upon CC or preceding secretion. CC -!- DISEASE: Defects in CILP are a cause of susceptibility to CC intervertebral disk disease (IDD) [MIM:603932]. A common musculo- CC skeletal disorder caused by degeneration of intervertebral disks CC of the lumbar spine. It results in low-back pain and unilateral CC leg pain. Note=Susceptibility to intervertebral disk disease, is CC conferred by variant p.Ile395Thr (PubMed:15864306). CC -!- MISCELLANEOUS: Antibodies against CILP are detected in patients CC with early-stage knee osteoarthritis and rheumatoid arthritis. CC -!- SIMILARITY: Contains 1 Ig-like C2-type (immunoglobulin-like) CC domain. CC -!- SIMILARITY: Contains 1 TSP type-1 domain. CC -!- CAUTION: Was originally thought to constitute the ATP CC pyrophosphatase enzyme (NTPPH). However, it was later shown CC (PubMed:12746903 and PubMed:15864306) that it is not the case. 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; AF035408; AAC33838.1; -; mRNA. DR EMBL; AB022430; BAA76692.1; -; Genomic_DNA. DR EMBL; AF035455; AAF14689.1; -; Genomic_DNA. DR EMBL; AF035448; AAF14689.1; JOINED; Genomic_DNA. DR EMBL; AF035451; AAF14689.1; JOINED; Genomic_DNA. DR EMBL; AF035453; AAF14689.1; JOINED; Genomic_DNA. DR EMBL; AF035449; AAF14689.1; JOINED; Genomic_DNA. DR EMBL; AY358904; AAQ89263.1; -; mRNA. DR EMBL; AK313352; BAG36154.1; -; mRNA. DR EMBL; AC068213; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC035776; AAH35776.1; -; mRNA. DR IPI; IPI00289275; -. DR PIR; T09484; T09484. DR RefSeq; NP_003604.3; NM_003613.3. DR UniGene; Hs.442180; -. DR ProteinModelPortal; O75339; -. DR SMR; O75339; 148-231, 311-399, 413-442. DR STRING; O75339; -. DR PhosphoSite; O75339; -. DR PRIDE; O75339; -. DR Ensembl; ENST00000261883; ENSP00000261883; ENSG00000138615. DR GeneID; 8483; -. DR KEGG; hsa:8483; -. DR CTD; 8483; -. DR GeneCards; GC15M042312; -. DR H-InvDB; HIX0202181; -. DR HGNC; HGNC:1980; CILP. DR HPA; HPA003195; -. DR MIM; 603489; gene. DR MIM; 603932; phenotype. DR neXtProt; NX_O75339; -. DR PharmGKB; PA26518; -. DR eggNOG; prNOG18093; -. DR GeneTree; ENSGT00390000008152; -. DR HOGENOM; HBG356500; -. DR HOVERGEN; HBG081175; -. DR InParanoid; O75339; -. DR OMA; NADCDAC; -. DR OrthoDB; EOG4F1X28; -. DR PhylomeDB; O75339; -. DR ArrayExpress; O75339; -. DR Bgee; O75339; -. DR CleanEx; HS_CILP; -. DR Genevestigator; O75339; -. DR GermOnline; ENSG00000138615; Homo sapiens. DR GO; GO:0044420; C:extracellular matrix part; IDA:BHF-UCL. DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL. DR GO; GO:0005578; C:proteinaceous extracellular matrix; IEA:UniProtKB-SubCell. DR GO; GO:0043569; P:negative regulation of insulin-like growth factor receptor signaling pathway; IDA:BHF-UCL. DR InterPro; IPR008969; CarboxyPept-like_regulatory. DR InterPro; IPR007110; Ig-like. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR013098; Ig_I-set. DR InterPro; IPR003598; Ig_sub2. DR InterPro; IPR000884; Thrombospondin_1_rpt. DR Gene3D; G3DSA:2.60.40.10; Ig-like_fold; 1. DR Pfam; PF07679; I-set; 1. DR Pfam; PF00090; TSP_1; 1. DR SMART; SM00408; IGc2; 1. DR SMART; SM00209; TSP1; 1. DR SUPFAM; SSF49464; CarboxypepD_reg; 1. DR SUPFAM; SSF82895; TSP1; 1. DR PROSITE; PS50835; IG_LIKE; 1. DR PROSITE; PS50092; TSP1; 1. PE 1: Evidence at protein level; KW Cleavage on pair of basic residues; Complete proteome; KW Direct protein sequencing; Disulfide bond; Extracellular matrix; KW Glycoprotein; Immunoglobulin domain; Polymorphism; Reference proteome; KW Secreted; Signal. FT SIGNAL 1 21 Potential. FT CHAIN 22 1184 Cartilage intermediate layer protein 1. FT /FTId=PRO_0000014671. FT CHAIN 22 ?724 Cartilage intermediate layer protein 1 FT C1. FT /FTId=PRO_0000014672. FT CHAIN ?725 1184 Cartilage intermediate layer protein 1 FT C2. FT /FTId=PRO_0000014673. FT DOMAIN 149 201 TSP type-1. FT DOMAIN 309 395 Ig-like C2-type. FT CARBOHYD 129 129 N-linked (GlcNAc...) (Potential). FT CARBOHYD 132 132 N-linked (GlcNAc...) (Potential). FT CARBOHYD 346 346 N-linked (GlcNAc...) (Probable). FT CARBOHYD 420 420 N-linked (GlcNAc...) (Potential). FT CARBOHYD 550 550 N-linked (GlcNAc...) (Potential). FT CARBOHYD 631 631 N-linked (GlcNAc...) (Potential). FT CARBOHYD 1000 1000 N-linked (GlcNAc...) (Potential). FT CARBOHYD 1056 1056 N-linked (GlcNAc...) (Potential). FT DISULFID 161 195 By similarity. FT DISULFID 165 200 By similarity. FT DISULFID 177 185 By similarity. FT DISULFID 330 376 By similarity. FT VARIANT 59 59 W -> L (in dbSNP:rs2585033). FT /FTId=VAR_022768. FT VARIANT 327 327 S -> F. FT /FTId=VAR_022769. FT VARIANT 395 395 I -> T (common polymorphism; associated FT with susceptibility to lumbar disk FT disease in Japanese; increases binding FT and inhibition of TGFB1; FT dbSNP:rs2073711). FT /FTId=VAR_022770. FT VARIANT 575 575 K -> E (in dbSNP:rs2679118). FT /FTId=VAR_022771. FT VARIANT 895 895 A -> V. FT /FTId=VAR_022772. FT VARIANT 979 979 Q -> R (in dbSNP:rs2679117). FT /FTId=VAR_022773. FT VARIANT 1101 1101 D -> N. FT /FTId=VAR_022774. FT VARIANT 1166 1166 G -> S (in dbSNP:rs938952). FT /FTId=VAR_022775. FT VARIANT 1168 1168 V -> A. FT /FTId=VAR_022776. FT CONFLICT 54 54 G -> M (in Ref. 1; AA sequence). FT CONFLICT 288 288 T -> D (in Ref. 1; AA sequence). FT CONFLICT 305 305 R -> D (in Ref. 1; AA sequence). FT CONFLICT 347 347 D -> T (in Ref. 1; AA sequence). SQ SEQUENCE 1184 AA; 132565 MW; 190B0316404D3B84 CRC64; MVGTKAWVFS FLVLEVTSVL GRQTMLTQSV RRVQPGKKNP SIFAKPADTL ESPGEWTTWF NIDYPGGKGD YERLDAIRFY YGDRVCARPL RLEARTTDWT PAGSTGQVVH GSPREGFWCL NREQRPGQNC SNYTVRFLCP PGSLRRDTER IWSPWSPWSK CSAACGQTGV QTRTRICLAE MVSLCSEASE EGQHCMGQDC TACDLTCPMG QVNADCDACM CQDFMLHGAV SLPGGAPASG AAIYLLTKTP KLLTQTDSDG RFRIPGLCPD GKSILKITKV KFAPIVLTMP KTSLKAATIK AEFVRAETPY MVMNPETKAR RAGQSVSLCC KATGKPRPDK YFWYHNDTLL DPSLYKHESK LVLRKLQQHQ AGEYFCKAQS DAGAVKSKVA QLIVIASDET PCNPVPESYL IRLPHDCFQN ATNSFYYDVG RCPVKTCAGQ QDNGIRCRDA VQNCCGISKT EEREIQCSGY TLPTKVAKEC SCQRCTETRS IVRGRVSAAD NGEPMRFGHV YMGNSRVSMT GYKGTFTLHV PQDTERLVLT FVDRLQKFVN TTKVLPFNKK GSAVFHEIKM LRRKKPITLE AMETNIIPLG EVVGEDPMAE LEIPSRSFYR QNGEPYIGKV KASVTFLDPR NISTATAAQT DLNFINDEGD TFPLRTYGMF SVDFRDEVTS EPLNAGKVKV HLDSTQVKMP EHISTVKLWS LNPDTGLWEE EGDFKFENQR RNKREDRTFL VGNLEIRERR LFNLDVPESR RCFVKVRAYR SERFLPSEQI QGVVISVINL EPRTGFLSNP RAWGRFDSVI TGPNGACVPA FCDDQSPDAY SAYVLASLAG EELQAVESSP KFNPNAIGVP QPYLNKLNYR RTDHEDPRVK KTAFQISMAK PRPNSAEESN GPIYAFENLR ACEEAPPSAA HFRFYQIEGD RYDYNTVPFN EDDPMSWTED YLAWWPKPME FRACYIKVKI VGPLEVNVRS RNMGGTHRQT VGKLYGIRDV RSTRDRDQPN VSAACLEFKC SGMLYDQDRV DRTLVKVIPQ GSCRRASVNP MLHEYLVNHL PLAVNNDTSE YTMLAPLDPL GHNYGIYTVT DQDPRTAKEI ALGRCFDGTS DGSSRIMKSN VGVALTFNCV ERQVGRQSAF QYLQSTPAQS PAAGTVQGRV PSRRQQRASR GGQRQGGVVA SLRFPRVAQQ PLIN //