TIMP1

TIMP1
PDBに登録されている構造
PDB	オルソログ検索: RCSB PDBe PDBj
PDBのIDコード一覧
	1D2B, 1OO9, 1UEA, 2J0T, 3MA2, 3V96
識別子
記号	TIMP1, CLGI, EPA, EPO, HCI, TIMP, TIMP-1, TIMP metallopeptidase inhibitor 1
外部ID	OMIM: 305370 MGI: 98752 HomoloGene: 36321 GeneCards: TIMP1
遺伝子の位置 (ヒト)
染色体	X染色体
終点	47,586,789 bp
遺伝子の位置 (マウス)
染色体	X染色体 (マウス)
終点	20,740,974 bp
RNA発現パターン
	さらなる参照発現データ
遺伝子オントロジー
分子機能	• peptidase inhibitor activity; • enzyme inhibitor activity; • cytokine activity; • 金属イオン結合; • protease binding; • 血漿タンパク結合; • metalloendopeptidase inhibitor activity; • growth factor activity; • zinc ion binding;
細胞の構成要素	• 細胞外マトリックス; • 細胞外領域; • 基底膜; • エキソソーム; • platelet alpha granule lumen; • 細胞外空間; • endoplasmic reticulum lumen; • コラーゲン;
生物学的プロセス	• response to cytokine; • negative regulation of peptidase activity; • 老化; • response to peptide hormone; • platelet degranulation; • 傷の治癒; • negative regulation of apoptotic process; • extracellular matrix disassembly; • negative regulation of trophoblast cell migration; • 有機物への反応; • cell activation; • 軟骨形成; • regulation of integrin-mediated signaling pathway; • positive regulation of cell population proliferation; • ホルモンへの反応; • negative regulation of membrane protein ectodomain proteolysis; • negative regulation of endopeptidase activity; • negative regulation of catalytic activity; • negative regulation of metallopeptidase activity; • 翻訳後修飾; • regulation of signaling receptor activity; • connective tissue replacement involved in inflammatory response wound healing; • サイトカイン媒介シグナル伝達経路;
	出典:Amigo / QuickGO
オルソログ
	7076
	21857
	ENSG00000102265
	ENSMUSG00000001131
	P01033,Q6FGX5
	P12032
	NM_003254
	NM_001044384; NM_001294280; NM_011593
	NP_003245; NP_003245.1
	NP_001037849; NP_001281209; NP_035723
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

TIMP1（tissue inhibitor of metalloproteinase 1）はTIMPファミリーに属するタンパク質であり、2つのドメインからなる約28 kDaの糖タンパク質である^[5]。TIMP1はいくつかの組織で発現している。

TIMP1は、細胞外マトリックスの分解に関与しているマトリックスメタロプロテアーゼ（MMP）に対する内因性阻害因子である。既知の大部分のMMPを阻害する役割に加えて、広範囲の細胞種に対して増殖を促進する能力を有し、また抗アポトーシス機能を有する可能性もある。

機能

TIMP1は、MMPやADAM、ADAMTSといったメタロプロテアーゼに対し、N末端ドメインが活性部位に結合することで阻害を行う^[6]。また、TIMP1のC末端ドメインは不活性な前駆体タンパク質であるpro-MMP-2やpro-MMP-9に結合することが示唆されている^[7]。TIMP1はMMPを調節することで、細胞外マトリックスの構成、創傷治癒^[8]、妊娠^[9]^[10]^[11]に重要に役割を果たしている。

TIMP1の活性調節の異常は、炎症、がん、線維症に関与していることが示唆されている^[12]^[13]^[14]。妊娠時には、TIMP1は着床過程、特に細胞性栄養膜細胞の子宮内膜への進入を調節する役割を果たしており^[15]、またMMPを阻害することで分娩時まで胎膜の完全性の維持に深く関与している^[16]。ノックアウトマウスを用いた研究では、TIMP-1が脳内における神経細胞死や軸索の発芽に関与していることが示唆されている^[17]。

細胞表面受容体への結合

TIMP1のC末端ドメインは、テトラスパニンCD63やCD82などの細胞表面受容体に結合することが示されている^[18]。これらの相互作用は、MAPK経路など下流のシグナル伝達経路を活性化する場合がある^[19]。

発現の調節

TIMP1遺伝子の転写は、多くのサイトカインやホルモンに応答して誘導される。この遺伝子はX染色体上に位置しているが、ヒト女性では不活性化されたX染色体の一部でこの遺伝子の発現がみられ、この遺伝子の不活性化には多様性があることが示唆されている。この遺伝子はシナプシンI遺伝子のイントロン6の内部に位置し、シナプシンIとは逆方向に転写される^[20]。

副腎皮質細胞では、副腎皮質刺激ホルモンによってTIMP1の発現は誘導され、TIMP1の発現上昇はコラゲナーゼ活性の低下と関連している^[21]。

TIMP1の発現上昇は、喉頭がん^[22]やメラノーマ^[23]など、さまざまながんにおいて予後不良と関連していることが知られている。前立腺がんや結腸がんにおいては、TIMP1の発現上昇はがん関連線維芽細胞の蓄積を促進し、腫瘍促進性微小環境の形成に寄与している^[24]。

出典

1 2 3 GRCh38: Ensembl release 89: ENSG00000102265 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000001131 - Ensembl, May 2017
↑ Human PubMed Reference:
↑ Mouse PubMed Reference:
↑ Nee LE, Mcmorrow T, Campbell E, Slattery C, Ryan MP (2004-10-01). “TNF-α and IL-1β–mediated regulation of MMP-9 and TIMP-1 in renal proximal tubular cells”. Kidney International 66 (4): 1376–1386. doi:10.1111/j.1523-1755.2004.00900.x. ISSN 0085-2538. PMID 15458430.
↑ Brew K, Nagase H (January 2010). “The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity”. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1803 (1): 55–71. doi:10.1016/j.bbamcr.2010.01.003. PMC 2853873. PMID 20080133.
↑ Olson MW, Gervasi DC, Mobashery S, Fridman R (1997-11-21). “Kinetic Analysis of the Binding of Human Matrix Metalloproteinase-2 and -9 to Tissue Inhibitor of Metalloproteinase (TIMP)-1 and TIMP-2*”. The Journal of Biological Chemistry 272 (47): 29975–29983. doi:10.1074/jbc.272.47.29975. ISSN 0021-9258. PMID 9368077.
↑ Brew K, Dinakarpandian D, Nagase H (March 2000). “Tissue inhibitors of metalloproteinases: evolution, structure and function”. Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 1477 (1–2): 267–283. doi:10.1016/S0167-4838(99)00279-4. PMID 10708863.
↑ Graham CH, Lala PK (August 1991). “Mechanism of control of trophoblast invasion in situ”. Journal of Cellular Physiology 148 (2): 228–234. doi:10.1002/jcp.1041480207. PMID 1652588.
↑ Nothnick WB, Soloway P, Curry TE (May 1997). “Assessment of the role of tissue inhibitor of metalloproteinase-1 (TIMP-1) during the periovulatory period in female mice lacking a functional TIMP-1 gene”. Biology of Reproduction 56 (5): 1181–1188. doi:10.1095/biolreprod56.5.1181. PMID 9160717.
↑ Nothnick WB (September 2000). “Disruption of the tissue inhibitor of metalloproteinase-1 gene results in altered reproductive cyclicity and uterine morphology in reproductive-age female mice”. Biology of Reproduction 63 (3): 905–912. doi:10.1095/biolreprod63.3.905. PMID 10952938.
↑ Schoeps B, Frädrich J, Krüger A (May 2023). “Cut loose TIMP-1: an emerging cytokine in inflammation”. Trends in Cell Biology 33 (5): 413–426. doi:10.1016/j.tcb.2022.08.005. ISSN 0962-8924. PMID 36163148.
↑ Takawale A, Zhang P, Patel VB, Wang X, Oudit G, Kassiri Z (June 2017). “Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myocardial Fibrosis by Mediating CD63–Integrin β1 Interaction”. Hypertension (Dallas, Tex.) 69 (6): 1092–1103. doi:10.1161/HYPERTENSIONAHA.117.09045. PMID 28373589.
↑ Kim YS, Kim SH, Kang JG, Ko JH (Nov 2012). “Expression level and glycan dynamics determine the net effects of TIMP-1 on cancer progression”. BMB Reports 45 (11): 623–628. doi:10.5483/BMBRep.2012.45.11.233. PMC 4133808. PMID 23187000.
↑ Graham CH, Lala PK (August 1991). “Mechanism of control of trophoblast invasion in situ”. Journal of Cellular Physiology 148 (2): 228–234. doi:10.1002/jcp.1041480207. PMID 1652588.
↑ Vincent ZL, Mitchell MD, Ponnampalam AP (December 2015). “Regulation of TIMP-1 in Human Placenta and Fetal Membranes by lipopolysaccharide and demethylating agent 5-aza-2'-deoxycytidine”. Reproductive Biology and Endocrinology 13. doi:10.1186/s12958-015-0132-y. PMC 4687108. PMID 26691525.
↑ Jourquin J, Tremblay E, Bernard A, Charton G, Chaillan FA, Marchetti E, Roman FS, Soloway PD, Dive V, Yiotakis A, Khrestchatisky M, Rivera S (November 2005). “Tissue inhibitor of metalloproteinases-1 (TIMP-1) modulates neuronal death, axonal plasticity, and learning and memory”. The European Journal of Neuroscience 22 (10): 2569–2578. doi:10.1111/j.1460-9568.2005.04426.x. PMID 16307599.
↑ Jung KK, Liu XW, Chirco R, Fridman R, Kim HR (2006-08-17). “Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein”. The EMBO Journal 25 (17): 3934–3942. doi:10.1038/sj.emboj.7601281. ISSN 0261-4189. PMC 1560352. PMID 16917503.
↑ Chirco R, Liu XW, Jung KK, Kim HR (March 2006). “Novel functions of TIMPs in cell signaling”. Cancer and Metastasis Reviews 25 (1): 99–113. doi:10.1007/s10555-006-7893-x. ISSN 0167-7659. PMID 16680576.
↑ “Entrez Gene: TIMP1 TIMP metallopeptidase inhibitor 1”. 2025年12月13日閲覧。
↑ Reichenstein M, Reich R, LeHoux JG, Hanukoglu I (February 2004). “ACTH induces TIMP-1 expression and inhibits collagenase in adrenal cortex cells”. Molecular and Cellular Endocrinology 215 (1–2): 109–114. doi:10.1016/j.mce.2003.11.011. PMID 15026182.
↑ Ma J, Wang J, Fan W, Pu X, Zhang D, Fan C, Xiong L, Zhu H, Xu N, Chen R, Liu S (Dec 2013). “Upregulated TIMP-1 correlates with poor prognosis of laryngeal squamous cell carcinoma”. International Journal of Clinical and Experimental Pathology 7 (1): 246–254. PMC 3885479. PMID 24427345.
↑ Tarhini AA, Lin Y, Yeku O, LaFramboise WA, Ashraf M, Sander C, Lee S, Kirkwood JM (January 2014). “A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma”. Journal of Translational Medicine 12: 19. doi:10.1186/1479-5876-12-19. PMC 3909384. PMID 24457057.
↑ Gong Y, Scott E, Lu R, Xu Y, Oh WK, Yu Q (2013-10-15). “TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression”. PLOS ONE 8 (10). Bibcode:2013PLoSO...877366G. doi:10.1371/journal.pone.0077366. PMC 3797040. PMID 24143225.

外部リンク

ペプチダーゼとインヒビターに関するMEROPSオンラインデータベース: I35.001
Overview of all the structural information available in the PDB for UniProt: P01033 (Metalloproteinase inhibitor 1) at the PDBe-KB.

[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000102265 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000001131 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

[:0-5] Nee LE, Mcmorrow T, Campbell E, Slattery C, Ryan MP (2004-10-01). “TNF-α and IL-1β–mediated regulation of MMP-9 and TIMP-1 in renal proximal tubular cells”. Kidney International 66 (4): 1376–1386. doi:10.1111/j.1523-1755.2004.00900.x. ISSN 0085-2538. PMID 15458430.

[:1-6] Brew K, Nagase H (January 2010). “The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity”. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1803 (1): 55–71. doi:10.1016/j.bbamcr.2010.01.003. PMC 2853873. PMID 20080133.

[:2-7] Olson MW, Gervasi DC, Mobashery S, Fridman R (1997-11-21). “Kinetic Analysis of the Binding of Human Matrix Metalloproteinase-2 and -9 to Tissue Inhibitor of Metalloproteinase (TIMP)-1 and TIMP-2*”. The Journal of Biological Chemistry 272 (47): 29975–29983. doi:10.1074/jbc.272.47.29975. ISSN 0021-9258. PMID 9368077.

[:3-8] Brew K, Dinakarpandian D, Nagase H (March 2000). “Tissue inhibitors of metalloproteinases: evolution, structure and function”. Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 1477 (1–2): 267–283. doi:10.1016/S0167-4838(99)00279-4. PMID 10708863.

[:4-9] Graham CH, Lala PK (August 1991). “Mechanism of control of trophoblast invasion in situ”. Journal of Cellular Physiology 148 (2): 228–234. doi:10.1002/jcp.1041480207. PMID 1652588.

[:5-10] Nothnick WB, Soloway P, Curry TE (May 1997). “Assessment of the role of tissue inhibitor of metalloproteinase-1 (TIMP-1) during the periovulatory period in female mice lacking a functional TIMP-1 gene”. Biology of Reproduction 56 (5): 1181–1188. doi:10.1095/biolreprod56.5.1181. PMID 9160717.

[:6-11] Nothnick WB (September 2000). “Disruption of the tissue inhibitor of metalloproteinase-1 gene results in altered reproductive cyclicity and uterine morphology in reproductive-age female mice”. Biology of Reproduction 63 (3): 905–912. doi:10.1095/biolreprod63.3.905. PMID 10952938.

[:7-12] Schoeps B, Frädrich J, Krüger A (May 2023). “Cut loose TIMP-1: an emerging cytokine in inflammation”. Trends in Cell Biology 33 (5): 413–426. doi:10.1016/j.tcb.2022.08.005. ISSN 0962-8924. PMID 36163148.

[:8-13] Takawale A, Zhang P, Patel VB, Wang X, Oudit G, Kassiri Z (June 2017). “Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myocardial Fibrosis by Mediating CD63–Integrin β1 Interaction”. Hypertension (Dallas, Tex.) 69 (6): 1092–1103. doi:10.1161/HYPERTENSIONAHA.117.09045. PMID 28373589.

[Kim_2012-14] Kim YS, Kim SH, Kang JG, Ko JH (Nov 2012). “Expression level and glycan dynamics determine the net effects of TIMP-1 on cancer progression”. BMB Reports 45 (11): 623–628. doi:10.5483/BMBRep.2012.45.11.233. PMC 4133808. PMID 23187000.

[:9-15] Graham CH, Lala PK (August 1991). “Mechanism of control of trophoblast invasion in situ”. Journal of Cellular Physiology 148 (2): 228–234. doi:10.1002/jcp.1041480207. PMID 1652588.

[:11-16] Vincent ZL, Mitchell MD, Ponnampalam AP (December 2015). “Regulation of TIMP-1 in Human Placenta and Fetal Membranes by lipopolysaccharide and demethylating agent 5-aza-2'-deoxycytidine”. Reproductive Biology and Endocrinology 13. doi:10.1186/s12958-015-0132-y. PMC 4687108. PMID 26691525.

[:10-17] Jourquin J, Tremblay E, Bernard A, Charton G, Chaillan FA, Marchetti E, Roman FS, Soloway PD, Dive V, Yiotakis A, Khrestchatisky M, Rivera S (November 2005). “Tissue inhibitor of metalloproteinases-1 (TIMP-1) modulates neuronal death, axonal plasticity, and learning and memory”. The European Journal of Neuroscience 22 (10): 2569–2578. doi:10.1111/j.1460-9568.2005.04426.x. PMID 16307599.

[:12-18] Jung KK, Liu XW, Chirco R, Fridman R, Kim HR (2006-08-17). “Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein”. The EMBO Journal 25 (17): 3934–3942. doi:10.1038/sj.emboj.7601281. ISSN 0261-4189. PMC 1560352. PMID 16917503.

[:13-19] Chirco R, Liu XW, Jung KK, Kim HR (March 2006). “Novel functions of TIMPs in cell signaling”. Cancer and Metastasis Reviews 25 (1): 99–113. doi:10.1007/s10555-006-7893-x. ISSN 0167-7659. PMID 16680576.

[20] “Entrez Gene: TIMP1 TIMP metallopeptidase inhibitor 1”. 2025年12月13日閲覧。

[Reichenstein_2004-21] Reichenstein M, Reich R, LeHoux JG, Hanukoglu I (February 2004). “ACTH induces TIMP-1 expression and inhibits collagenase in adrenal cortex cells”. Molecular and Cellular Endocrinology 215 (1–2): 109–114. doi:10.1016/j.mce.2003.11.011. PMID 15026182.

[pmid_=_24427345-22] Ma J, Wang J, Fan W, Pu X, Zhang D, Fan C, Xiong L, Zhu H, Xu N, Chen R, Liu S (Dec 2013). “Upregulated TIMP-1 correlates with poor prognosis of laryngeal squamous cell carcinoma”. International Journal of Clinical and Experimental Pathology 7 (1): 246–254. PMC 3885479. PMID 24427345.

[pmid_=_24457057-23] Tarhini AA, Lin Y, Yeku O, LaFramboise WA, Ashraf M, Sander C, Lee S, Kirkwood JM (January 2014). “A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma”. Journal of Translational Medicine 12: 19. doi:10.1186/1479-5876-12-19. PMC 3909384. PMID 24457057.

[24] Gong Y, Scott E, Lu R, Xu Y, Oh WK, Yu Q (2013-10-15). “TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression”. PLOS ONE 8 (10). Bibcode:2013PLoSO...877366G. doi:10.1371/journal.pone.0077366. PMC 3797040. PMID 24143225.

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TIMP1

機能

細胞表面受容体への結合

発現の調節

出典

関連文献

関連項目

外部リンク