ID   TIMP2_RAT               Reviewed;         220 AA.
AC   P30121; Q546J4;
DT   01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1996, sequence version 3.
DT   24-JAN-2024, entry version 169.
DE   RecName: Full=Metalloproteinase inhibitor 2;
DE   AltName: Full=Tissue inhibitor of metalloproteinases 2;
DE            Short=TIMP-2;
DE   Flags: Precursor;
GN   Name=Timp2; Synonyms=Timp-2;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=Sprague-Dawley; TISSUE=Bone;
RX   PubMed=8203893; DOI=10.1006/abbi.1994.1243;
RA   Cook T.F., Burke J.S., Bergman K.D., Quinn C.O., Jeffrey J.J.,
RA   Partridge N.C.;
RT   "Cloning and regulation of rat tissue inhibitor of metalloproteinases-2 in
RT   osteoblastic cells.";
RL   Arch. Biochem. Biophys. 311:313-320(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Mammary gland;
RA   Gibbons K.L., O'Grady R.L., Piper A.A.;
RL   Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=8050496; DOI=10.1006/excr.1994.1215;
RA   Santoro M., Battaglia C., Zhang L., Carlomagno F., Martelli M.L.,
RA   Salvatore D., Fusco A.;
RT   "Cloning of the rat tissue inhibitor of metalloproteinases type 2 (TIMP-2)
RT   gene: analysis of its expression in normal and transformed thyroid cells.";
RL   Exp. Cell Res. 213:398-403(1994).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Testis;
RX   PubMed=8792217;
RA   Grima J., Calcagno K., Cheng C.Y.;
RT   "Purification, cDNA cloning, and developmental changes in the steady-state
RT   mRNA level of rat testicular tissue inhibitor of metalloproteases-2 (TIMP-
RT   2).";
RL   J. Androl. 17:263-275(1996).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=Sprague-Dawley; TISSUE=Heart;
RX   PubMed=11684074; DOI=10.1016/s0008-6363(01)00398-4;
RA   Briest W., Hoelzl A., Rassler B., Deten A., Leicht M., Baba H.A.,
RA   Zimmer H.G.;
RT   "Cardiac remodeling after long term norepinephrine treatment in rats.";
RL   Cardiovasc. Res. 52:265-273(2001).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   PROTEIN SEQUENCE OF 27-48.
RX   PubMed=1309971; DOI=10.1016/0003-9861(92)90009-l;
RA   Roswit W.T., McCourt D.W., Partridge N.C., Jeffrey J.J.;
RT   "Purification and sequence analysis of two rat tissue inhibitors of
RT   metalloproteinases.";
RL   Arch. Biochem. Biophys. 292:402-410(1992).
CC   -!- FUNCTION: Complexes with metalloproteinases (such as collagenases) and
CC       irreversibly inactivates them by binding to their catalytic zinc
CC       cofactor.
CC   -!- SUBUNIT: Interacts (via the C-terminal) with MMP2 (via the C-terminal
CC       PEX domain); the interaction inhibits the MMP2 activity. {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Secreted.
CC   -!- PTM: The activity of TIMP2 is dependent on the presence of disulfide
CC       bonds.
CC   -!- SIMILARITY: Belongs to the protease inhibitor I35 (TIMP) family.
CC       {ECO:0000305}.
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DR   EMBL; U14526; AAA21553.1; -; mRNA.
DR   EMBL; L31884; AAA84581.1; -; mRNA.
DR   EMBL; S72594; AAC60687.1; -; mRNA.
DR   EMBL; S82718; AAB49507.1; -; mRNA.
DR   EMBL; AJ409332; CAC35060.1; -; mRNA.
DR   EMBL; BC084714; AAH84714.1; -; mRNA.
DR   PIR; S45683; S45683.
DR   RefSeq; NP_068824.1; NM_021989.2.
DR   AlphaFoldDB; P30121; -.
DR   BMRB; P30121; -.
DR   SMR; P30121; -.
DR   CORUM; P30121; -.
DR   STRING; 10116.ENSRNOP00000004290; -.
DR   MEROPS; I35.002; -.
DR   PhosphoSitePlus; P30121; -.
DR   PaxDb; 10116-ENSRNOP00000004290; -.
DR   Ensembl; ENSRNOT00000004290.5; ENSRNOP00000004290.4; ENSRNOG00000033143.2.
DR   Ensembl; ENSRNOT00055055187; ENSRNOP00055045611; ENSRNOG00055031858.
DR   Ensembl; ENSRNOT00060053062; ENSRNOP00060044112; ENSRNOG00060030518.
DR   Ensembl; ENSRNOT00065007292; ENSRNOP00065005067; ENSRNOG00065004980.
DR   GeneID; 29543; -.
DR   KEGG; rno:29543; -.
DR   UCSC; RGD:61312; rat.
DR   AGR; RGD:61312; -.
DR   CTD; 7077; -.
DR   RGD; 61312; Timp2.
DR   eggNOG; KOG4745; Eukaryota.
DR   GeneTree; ENSGT00940000153123; -.
DR   HOGENOM; CLU_084029_0_0_1; -.
DR   InParanoid; P30121; -.
DR   OMA; SAQDECL; -.
DR   OrthoDB; 5403389at2759; -.
DR   PhylomeDB; P30121; -.
DR   Reactome; R-RNO-1592389; Activation of Matrix Metalloproteinases.
DR   Reactome; R-RNO-6798695; Neutrophil degranulation.
DR   PRO; PR:P30121; -.
DR   Proteomes; UP000002494; Chromosome 10.
DR   Bgee; ENSRNOG00000003148; Expressed in lung and 20 other cell types or tissues.
DR   GO; GO:0005604; C:basement membrane; ISO:RGD.
DR   GO; GO:0009986; C:cell surface; IDA:RGD.
DR   GO; GO:0031012; C:extracellular matrix; IBA:GO_Central.
DR   GO; GO:0005615; C:extracellular space; IDA:RGD.
DR   GO; GO:0030426; C:growth cone; IDA:RGD.
DR   GO; GO:0043025; C:neuronal cell body; IDA:RGD.
DR   GO; GO:0008047; F:enzyme activator activity; ISO:RGD.
DR   GO; GO:0005178; F:integrin binding; IPI:RGD.
DR   GO; GO:0008191; F:metalloendopeptidase inhibitor activity; IMP:RGD.
DR   GO; GO:0140678; F:molecular function inhibitor activity; ISO:RGD.
DR   GO; GO:0030414; F:peptidase inhibitor activity; ISO:RGD.
DR   GO; GO:0002020; F:protease binding; ISO:RGD.
DR   GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR   GO; GO:0071310; P:cellular response to organic substance; ISO:RGD.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:RGD.
DR   GO; GO:0051045; P:negative regulation of membrane protein ectodomain proteolysis; IBA:GO_Central.
DR   GO; GO:0045930; P:negative regulation of mitotic cell cycle; IDA:RGD.
DR   GO; GO:0045861; P:negative regulation of proteolysis; IMP:RGD.
DR   GO; GO:0046580; P:negative regulation of Ras protein signal transduction; IDA:RGD.
DR   GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:RGD.
DR   GO; GO:0045666; P:positive regulation of neuron differentiation; IDA:RGD.
DR   GO; GO:0043408; P:regulation of MAPK cascade; ISO:RGD.
DR   GO; GO:0045664; P:regulation of neuron differentiation; ISO:RGD.
DR   GO; GO:0032487; P:regulation of Rap protein signal transduction; IDA:RGD.
DR   GO; GO:0034097; P:response to cytokine; IEP:RGD.
DR   GO; GO:0009725; P:response to hormone; IBA:GO_Central.
DR   GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR   GO; GO:0007283; P:spermatogenesis; NAS:RGD.
DR   CDD; cd03585; NTR_TIMP; 1.
DR   Gene3D; 2.40.50.120; -; 1.
DR   Gene3D; 3.90.370.10; Tissue inhibitor of metalloproteinase-1. Chain B, domain 1; 1.
DR   InterPro; IPR001134; Netrin_domain.
DR   InterPro; IPR001820; TIMP.
DR   InterPro; IPR008993; TIMP-like_OB-fold.
DR   InterPro; IPR027465; TIMP_C.
DR   InterPro; IPR030490; TIMP_CS.
DR   PANTHER; PTHR11844; METALLOPROTEASE INHIBITOR; 1.
DR   PANTHER; PTHR11844:SF24; METALLOPROTEINASE INHIBITOR 2; 1.
DR   Pfam; PF00965; TIMP; 1.
DR   SMART; SM00206; NTR; 1.
DR   SUPFAM; SSF50242; TIMP-like; 1.
DR   PROSITE; PS50189; NTR; 1.
DR   PROSITE; PS00288; TIMP; 1.
DR   Genevisible; P30121; RN.
PE   1: Evidence at protein level;
KW   Direct protein sequencing; Disulfide bond; Metal-binding;
KW   Metalloenzyme inhibitor; Metalloprotease inhibitor; Protease inhibitor;
KW   Reference proteome; Secreted; Signal; Zinc.
FT   SIGNAL          1..26
FT                   /evidence="ECO:0000269|PubMed:1309971"
FT   CHAIN           27..220
FT                   /note="Metalloproteinase inhibitor 2"
FT                   /id="PRO_0000034337"
FT   DOMAIN          27..152
FT                   /note="NTR"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT   REGION          27..30
FT                   /note="Involved in metalloproteinase-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P16035"
FT   REGION          95..96
FT                   /note="Involved in metalloproteinase-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P16035"
FT   BINDING         27
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="ligand shared with metalloproteinase partner"
FT                   /evidence="ECO:0000250|UniProtKB:P16035"
FT   SITE            40
FT                   /note="Involved in metalloproteinase-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P16035"
FT   SITE            61
FT                   /note="Involved in metalloproteinase-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P16035"
FT   SITE            67
FT                   /note="Involved in metalloproteinase-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P16035"
FT   DISULFID        27..98
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT   DISULFID        29..127
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT   DISULFID        39..152
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT   DISULFID        154..201
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT   DISULFID        159..164
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT   DISULFID        172..193
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00295"
FT   CONFLICT        7
FT                   /note="S -> T (in Ref. 1; AAA21553)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        153
FT                   /note="E -> Q (in Ref. 1; AAA21553)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   220 AA;  24356 MW;  1C97A3F050C3AE7D CRC64;
     MGAAARSLRL ALGLLLLATL LRPADACSCS PVHPQQAFCN ADVVIRAKAV SEKEVDSGND
     IYGNPIKRIQ YEIKQIKMFK GPDKDIEFIY TAPSSAVCGV SLDVGGKKEY LIAGKAEGDG
     KMHITLCDFI VPWDTLSITQ KKSLNHRYQM GCECKITRCP MIPCYISSPD ECLWMDWVTE
     KSINGHQAKF FACIKRSDGS CAWYRGAAPP KQEFLDIEDP
//