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Q99969

- RARR2_HUMAN

UniProt

Q99969 - RARR2_HUMAN

Protein

Retinoic acid receptor responder protein 2

Gene

RARRES2

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 113 (01 Oct 2014)
      Sequence version 1 (01 May 1997)
      Previous versions | rss
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    Functioni

    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.7 Publications

    GO - Molecular functioni

    1. protein binding Source: UniProtKB
    2. receptor binding Source: UniProtKB

    GO - Biological processi

    1. brown fat cell differentiation Source: Ensembl
    2. chemotaxis Source: UniProtKB-KW
    3. embryonic digestive tract development Source: DFLAT
    4. inflammatory response Source: UniProtKB-KW
    5. in utero embryonic development Source: DFLAT
    6. positive regulation of chemotaxis Source: UniProtKB
    7. positive regulation of fat cell differentiation Source: UniProtKB
    8. positive regulation of glucose import in response to insulin stimulus Source: UniProtKB
    9. positive regulation of macrophage chemotaxis Source: DFLAT
    10. positive regulation of protein phosphorylation Source: UniProtKB
    11. regulation of lipid catabolic process Source: UniProtKB
    12. retinoid metabolic process Source: UniProtKB

    Keywords - Biological processi

    Chemotaxis, Differentiation, Inflammatory response

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Retinoic acid receptor responder protein 2
    Alternative name(s):
    Chemerin
    RAR-responsive protein TIG2
    Tazarotene-induced gene 2 protein
    Gene namesi
    Name:RARRES2
    Synonyms:TIG2
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 7

    Organism-specific databases

    HGNCiHGNC:9868. RARRES2.

    Subcellular locationi

    Secreted Curated

    GO - Cellular componenti

    1. extracellular matrix Source: DFLAT
    2. extracellular region Source: UniProtKB
    3. extracellular vesicular exosome Source: UniProt

    Keywords - Cellular componenti

    Secreted

    Pathology & Biotechi

    Organism-specific databases

    PharmGKBiPA34229.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 20201 PublicationAdd
    BLAST
    Chaini21 – 157137Retinoic acid receptor responder protein 2PRO_0000022529Add
    BLAST
    Propeptidei158 – 1636PRO_0000424870

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi77 ↔ 87By similarity
    Disulfide bondi98 ↔ 117By similarity
    Disulfide bondi101 ↔ 135Sequence Analysis

    Post-translational modificationi

    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).2 Publications

    Keywords - PTMi

    Disulfide bond

    Proteomic databases

    MaxQBiQ99969.
    PaxDbiQ99969.
    PeptideAtlasiQ99969.
    PRIDEiQ99969.

    Expressioni

    Tissue specificityi

    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.3 Publications

    Inductioni

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

    Gene expression databases

    ArrayExpressiQ99969.
    BgeeiQ99969.
    CleanExiHS_RARRES2.
    GenevestigatoriQ99969.

    Organism-specific databases

    HPAiHPA049359.

    Interactioni

    Protein-protein interaction databases

    STRINGi9606.ENSP00000223271.

    Structurei

    3D structure databases

    ProteinModelPortaliQ99969.
    SMRiQ99969. Positions 26-105.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Keywords - Domaini

    Signal

    Phylogenomic databases

    eggNOGiNOG43952.
    HOGENOMiHOG000093205.
    HOVERGENiHBG000698.
    InParanoidiQ99969.
    KOiK10044.
    OMAiYYFPGQF.
    OrthoDBiEOG7B05FP.
    PhylomeDBiQ99969.
    TreeFamiTF330938.

    Family and domain databases

    InterProiIPR029562. Chemerin.
    [Graphical view]
    PANTHERiPTHR15106:SF2. PTHR15106:SF2. 1 hit.

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    Q99969-1 [UniParc]FASTAAdd to Basket

    « Hide

    MRRLLIPLAL WLGAVGVGVA ELTEAQRRGL QVALEEFHKH PPVQWAFQET    50
    SVESAVDTPF PAGIFVRLEF KLQQTSCRKR DWKKPECKVR PNGRKRKCLA 100
    CIKLGSEDKV LGRLVHCPIE TQVLREAEEH QETQCLRVQR AGEDPHSFYF 150
    PGQFAFSKAL PRS 163
    Length:163
    Mass (Da):18,618
    Last modified:May 1, 1997 - v1
    Checksum:iA96EB7D0999EC3DB
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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.
    CCDSiCCDS5902.1.
    RefSeqiNP_002880.1. NM_002889.3.
    UniGeneiHs.647064.

    Genome annotation databases

    EnsembliENST00000223271; ENSP00000223271; ENSG00000106538.
    ENST00000466675; ENSP00000418009; ENSG00000106538.
    ENST00000482669; ENSP00000418483; ENSG00000106538.
    GeneIDi5919.
    KEGGihsa:5919.
    UCSCiuc003wha.3. human.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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 .
    CCDSi CCDS5902.1.
    RefSeqi NP_002880.1. NM_002889.3.
    UniGenei Hs.647064.

    3D structure databases

    ProteinModelPortali Q99969.
    SMRi Q99969. Positions 26-105.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    STRINGi 9606.ENSP00000223271.

    Proteomic databases

    MaxQBi Q99969.
    PaxDbi Q99969.
    PeptideAtlasi Q99969.
    PRIDEi Q99969.

    Protocols and materials databases

    DNASUi 5919.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000223271 ; ENSP00000223271 ; ENSG00000106538 .
    ENST00000466675 ; ENSP00000418009 ; ENSG00000106538 .
    ENST00000482669 ; ENSP00000418483 ; ENSG00000106538 .
    GeneIDi 5919.
    KEGGi hsa:5919.
    UCSCi uc003wha.3. human.

    Organism-specific databases

    CTDi 5919.
    GeneCardsi GC07M150035.
    HGNCi HGNC:9868. RARRES2.
    HPAi HPA049359.
    MIMi 601973. gene.
    neXtProti NX_Q99969.
    PharmGKBi PA34229.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG43952.
    HOGENOMi HOG000093205.
    HOVERGENi HBG000698.
    InParanoidi Q99969.
    KOi K10044.
    OMAi YYFPGQF.
    OrthoDBi EOG7B05FP.
    PhylomeDBi Q99969.
    TreeFami TF330938.

    Miscellaneous databases

    GeneWikii Chemerin.
    GenomeRNAii 5919.
    NextBioi 23048.
    PROi Q99969.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q99969.
    Bgeei Q99969.
    CleanExi HS_RARRES2.
    Genevestigatori Q99969.

    Family and domain databases

    InterProi IPR029562. Chemerin.
    [Graphical view ]
    PANTHERi PTHR15106:SF2. PTHR15106:SF2. 1 hit.
    ProtoNeti Search...

    Publicationsi

    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.
      , 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.
      , 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. 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. 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. Cited for: FUNCTION, TISSUE SPECIFICITY.

    Entry informationi

    Entry nameiRARR2_HUMAN
    AccessioniPrimary (citable) accession number: Q99969
    Secondary accession number(s): Q7LE02
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: May 30, 2000
    Last sequence update: May 1, 1997
    Last modified: October 1, 2014
    This is version 113 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (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.

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 7
      Human chromosome 7: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

    External Data

    Dasty 3