Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q99969 (RARR2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 111. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Retinoic acid receptor responder protein 2
Alternative name(s):
Chemerin
RAR-responsive protein TIG2
Tazarotene-induced gene 2 protein
Gene names
Name:RARRES2
Synonyms:TIG2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length163 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Adipocyte-secreted protein (adipokine) that regulates adipogenesis, metabolism and inflammation through activation of the chemokine-like receptor 1 (CMKLR1). Its other ligands include G protein-coupled receptor 1 (GPR1) and chemokine receptor-like 2 (CCRL2). Positively regulates adipocyte differentiation, modulates the expression of adipocyte genes involved in lipid and glucose metabolism and might play a role in angiogenesis, a process essential for the expansion of white adipose tissue. Also acts as a proinflammatory adipokine, causing an increase in secretion of proinflammatory and prodiabetic adipokines, which further impair adipose tissue metabolic function and have negative systemic effects including impaired insulin sensitivity, altered glucose and lipid metabolism, and a decrease in vascular function in other tissues. Can have both pro- and anti-inflammatory properties depending on the modality of enzymatic cleavage by different classes of proteases. Acts as a chemotactic factor for leukocyte populations expressing CMKLR1, particularly immature plasmacytoid dendritic cells, but also immature myeloid DCs, macrophages and natural killer cells. Exerts an anti-inflammatory role by preventing TNF/TNFA-induced VCAM1 expression and monocytes adhesion in vascular endothelial cells. The effect is mediated via inhibiting activation of NF-kappa-B and CRK/p38 through stimulation of AKT1/NOS3 signaling and nitric oxide production. Its dual role in inflammation and metabolism might provide a link between chronic inflammation and obesity, as well as obesity-related disorders such as type 2 diabetes and cardiovascular disease. Exhibits an antimicrobial function in the skin. Ref.8 Ref.10 Ref.11 Ref.12 Ref.14 Ref.17 Ref.20

Subcellular location

Secreted Potential Ref.12.

Tissue specificity

Expressed at the highest levels in placenta, liver, and white adipose tissue (WAT), and to a lesser extent in many other tissues such as lung, brown adipose tissue, heart, ovary, kidney, skeletal muscle and pancreas. Within WAT, expression is enriched in adipocytes as compared to the stromal vascular fraction. Expression and secretion increases dramatically with adipogenesis. Highly expressed in skin (basal and suprabasal layers of the epidermis, hair follicles and endothelial cells). Expression is elevated in numerous metabolic and inflammatory diseases including psoriasis, obesity, type 2 diabetes, metabolic syndrome and cardiovascular disease. Ref.10 Ref.11 Ref.20

Induction

Inhibited in psoriatic lesions. Activated by tazarotene in skin rafts and in the epidermis of psoriatic lesions. Ref.1

Post-translational modification

Secreted in an inactive precursor form, prochemerin, which is proteolytically processed by a variety of extracellular proteases to generate forms with differing levels of bioactivity. For example, the removal of six amino acids results in chemerin-157, which exhibits the highest activity, while removal of seven amino acids results in chemerin-156 which has slightly less activity. Some proteases are able to cleave at more than one site and chemerin forms may be sequentially processed by different enzymes to modulate activity levels. The coordinated expression and activity of chemerin-modifying enzymes is essential for regulating its bioactivation, inactivation and, consequently, biological function. Cathepsin G cleaves seven C-terminal amino acids from prochemerin (chemerin-156), elastase is able to cleave six (chemerin-157), eight (chemerin-155) or eleven (chemerin-152), plasmin cleaves five amino acids (chemerin-158), and tryptase cleaves five (chemerin-158) or eight (chemerin-155). Multiple cleavages might be required to fully activate chemerin, with an initial tryptase cleavage resulting in chemerin with low activity (chemerin-158), and a second cleavage by carboxypeptidase N or B producing highly active chemerin (chemerin-157).

Ontologies

Keywords
   Biological processChemotaxis
Differentiation
Inflammatory response
   Cellular componentSecreted
   DomainSignal
   PTMDisulfide bond
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processbrown fat cell differentiation

Inferred from electronic annotation. Source: Ensembl

chemotaxis

Inferred from electronic annotation. Source: UniProtKB-KW

embryonic digestive tract development

Inferred from mutant phenotype PubMed 19443732. Source: DFLAT

in utero embryonic development

Inferred from expression pattern PubMed 19443732. Source: DFLAT

inflammatory response

Inferred from electronic annotation. Source: UniProtKB-KW

positive regulation of chemotaxis

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of fat cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of glucose import in response to insulin stimulus

Inferred from direct assay Ref.12. Source: UniProtKB

positive regulation of macrophage chemotaxis

Inferred from mutant phenotype PubMed 19443732. Source: DFLAT

positive regulation of protein phosphorylation

Inferred from direct assay Ref.11. Source: UniProtKB

regulation of lipid catabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

retinoid metabolic process

Inferred from direct assay Ref.1. Source: UniProtKB

   Cellular_componentextracellular matrix

Inferred from direct assay PubMed 19443732. Source: DFLAT

extracellular region

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionprotein binding

Inferred from physical interaction PubMed 14530373. Source: UniProtKB

receptor binding

Inferred from physical interaction PubMed 14530373. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2020 Ref.8
Chain21 – 157137Retinoic acid receptor responder protein 2
PRO_0000022529
Propeptide158 – 1636
PRO_0000424870

Amino acid modifications

Disulfide bond77 ↔ 87 By similarity
Disulfide bond98 ↔ 117 By similarity
Disulfide bond101 ↔ 135 Potential

Sequences

Sequence LengthMass (Da)Tools
Q99969 [UniParc].

Last modified May 1, 1997. Version 1.
Checksum: A96EB7D0999EC3DB

FASTA16318,618
        10         20         30         40         50         60 
MRRLLIPLAL WLGAVGVGVA ELTEAQRRGL QVALEEFHKH PPVQWAFQET SVESAVDTPF 

        70         80         90        100        110        120 
PAGIFVRLEF KLQQTSCRKR DWKKPECKVR PNGRKRKCLA CIKLGSEDKV LGRLVHCPIE 

       130        140        150        160 
TQVLREAEEH QETQCLRVQR AGEDPHSFYF PGQFAFSKAL PRS 

« Hide

References

« Hide 'large scale' references
[1]"Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin."
Nagpal S., Patel S., Jacobe H., DiSepio D., Ghosn C., Malhotra M., Teng M., Duvic M., Chandraratna R.A.S.
J. Invest. Dermatol. 109:91-95(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], INDUCTION.
Tissue: Skin.
[2]"Selection of cDNAs encoding putative type II membrane proteins on the cell surface from a human full-length cDNA bank."
Yokoyama-Kobayashi M., Yamaguchi T., Sekine S., Kato S.
Gene 228:161-167(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Gastric adenocarcinoma.
[3]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Prostate.
[4]"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)."
Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.
Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]"The DNA sequence of human chromosome 7."
Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. expand/collapse author list , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K.
Nature 424:157-164(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Kidney.
[8]"Characterization of human circulating TIG2 as a ligand for the orphan receptor ChemR23."
Meder W., Wendland M., Busmann A., Kutzleb C., Spodsberg N., John H., Richter R., Schleuder D., Meyer M., Forssmann W.G.
FEBS Lett. 555:495-499(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 21-67, PROTEOLYTIC PROCESSING, FUNCTION AS LIGAND FOR CMKLR1.
[9]"Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades."
Zabel B.A., Allen S.J., Kulig P., Allen J.A., Cichy J., Handel T.M., Butcher E.C.
J. Biol. Chem. 280:34661-34666(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEOLYTIC PROCESSING, IDENTIFICATION BY MASS SPECTROMETRY.
[10]"Chemerin--a new adipokine that modulates adipogenesis via its own receptor."
Roh S.G., Song S.H., Choi K.C., Katoh K., Wittamer V., Parmentier M., Sasaki S.
Biochem. Biophys. Res. Commun. 362:1013-1018(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY.
[11]"Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism."
Goralski K.B., McCarthy T.C., Hanniman E.A., Zabel B.A., Butcher E.C., Parlee S.D., Muruganandan S., Sinal C.J.
J. Biol. Chem. 282:28175-28188(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY.
[12]"Chemerin enhances insulin signaling and potentiates insulin-stimulated glucose uptake in 3T3-L1 adipocytes."
Takahashi M., Takahashi Y., Takahashi K., Zolotaryov F.N., Hong K.S., Kitazawa R., Iida K., Okimura Y., Kaji H., Kitazawa S., Kasuga M., Chihara K.
FEBS Lett. 582:573-578(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[13]"Proteolytic regulatory mechanism of chemerin bioactivity."
Du X.Y., Leung L.L.
Acta Biochim. Biophys. Sin. 41:973-979(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON PROTEOLYTIC PROCESSING.
[14]"Chemerin, a novel adipokine in the regulation of angiogenesis."
Bozaoglu K., Curran J.E., Stocker C.J., Zaibi M.S., Segal D., Konstantopoulos N., Morrison S., Carless M., Dyer T.D., Cole S.A., Goring H.H., Moses E.K., Walder K., Cawthorne M.A., Blangero J., Jowett J.B.
J. Clin. Endocrinol. Metab. 95:2476-2485(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[15]"Chemerin: at the crossroads of inflammation and obesity."
Ernst M.C., Sinal C.J.
Trends Endocrinol. Metab. 21:660-667(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[16]"Chemerin and its receptors in leukocyte trafficking, inflammation and metabolism."
Bondue B., Wittamer V., Parmentier M.
Cytokine Growth Factor Rev. 22:331-338(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[17]"A novel adipocytokine, chemerin exerts anti-inflammatory roles in human vascular endothelial cells."
Yamawaki H., Kameshima S., Usui T., Okada M., Hara Y.
Biochem. Biophys. Res. Commun. 423:152-157(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[18]"Chemerin: a potential endocrine link between obesity and type 2 diabetes."
Roman A.A., Parlee S.D., Sinal C.J.
Endocrine 42:243-251(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[19]"Towards an integrative approach to understanding the role of chemerin in human health and disease."
Rourke J.L., Dranse H.J., Sinal C.J.
Obes. Rev. 14:245-262(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[20]"Chemerin is an antimicrobial agent in human epidermis."
Banas M., Zabieglo K., Kasetty G., Kapinska-Mrowiecka M., Borowczyk J., Drukala J., Murzyn K., Zabel B.A., Butcher E.C., Schroeder J.M., Schmidtchen A., Cichy J.
PLoS ONE 8:E58709-E58709(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U77594 mRNA. Translation: AAB47975.1.
AB015632 mRNA. Translation: BAA76499.1.
AK312197 mRNA. Translation: BAG35130.1.
CR541992 mRNA. Translation: CAG46789.1.
CR542026 mRNA. Translation: CAG46823.1.
AC005586 Genomic DNA. Translation: AAS00384.1.
CH471173 Genomic DNA. Translation: EAW54120.1.
CH471173 Genomic DNA. Translation: EAW54121.1.
BC000069 mRNA. Translation: AAH00069.1.
CCDSCCDS5902.1.
RefSeqNP_002880.1. NM_002889.3.
UniGeneHs.647064.

3D structure databases

ProteinModelPortalQ99969.
SMRQ99969. Positions 26-105.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

STRING9606.ENSP00000223271.

Proteomic databases

MaxQBQ99969.
PaxDbQ99969.
PeptideAtlasQ99969.
PRIDEQ99969.

Protocols and materials databases

DNASU5919.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000223271; ENSP00000223271; ENSG00000106538.
ENST00000466675; ENSP00000418009; ENSG00000106538.
ENST00000482669; ENSP00000418483; ENSG00000106538.
GeneID5919.
KEGGhsa:5919.
UCSCuc003wha.3. human.

Organism-specific databases

CTD5919.
GeneCardsGC07M150035.
HGNCHGNC:9868. RARRES2.
HPAHPA049359.
MIM601973. gene.
neXtProtNX_Q99969.
PharmGKBPA34229.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG43952.
HOGENOMHOG000093205.
HOVERGENHBG000698.
InParanoidQ99969.
KOK10044.
OMAYYFPGQF.
OrthoDBEOG7B05FP.
PhylomeDBQ99969.
TreeFamTF330938.

Gene expression databases

ArrayExpressQ99969.
BgeeQ99969.
CleanExHS_RARRES2.
GenevestigatorQ99969.

Family and domain databases

ProtoNetSearch...

Other

GeneWikiChemerin.
GenomeRNAi5919.
NextBio23048.
PROQ99969.
SOURCESearch...

Entry information

Entry nameRARR2_HUMAN
AccessionPrimary (citable) accession number: Q99969
Secondary accession number(s): Q7LE02
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: May 1, 1997
Last modified: July 9, 2014
This is version 111 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 7

Human chromosome 7: entries, gene names and cross-references to MIM