MMP14

Matrix metalloproteinase-14 (MMP14), also known as MT1-MMP, is a zinc-dependent type I transmembrane metalloproteinase characterized by a modular structure that enables its diverse biological functions. The protein comprises an extracellular catalytic domain responsible for matrix degradation, a short 20-amino acid cytoplasmic tail, and a single transmembrane domain anchoring it to the cell membrane.{{cite journal | vauthors = Attur M, Lu C, Zhang X, Han T, Alexandre C, Valacca C, Zheng S, Meikle S, Dabovic BB, Tassone E, Yang Q, Kolupaeva V, Yakar S, Abramson S, Mignatti P | title = Membrane-type 1 Matrix Metalloproteinase Modulates Tissue Homeostasis by a Non-proteolytic Mechanism | journal = iScience | volume = 23 | issue = 12 | pages = 101789 | date = December 2020 | pmid = 33294797 | pmc = 7695985 | doi = 10.1016/j.isci.2020.101789 | bibcode = 2020iSci...23j1789A }}{{cite journal | vauthors = Eisenach PA, de Sampaio PC, Murphy G, Roghi C | title = Membrane type 1 matrix metalloproteinase (MT1-MMP) ubiquitination at Lys581 increases cellular invasion through type I collagen | journal = The Journal of Biological Chemistry | volume = 287 | issue = 14 | pages = 11533–45 | date = March 2012 | pmid = 22315223 | pmc = 3322893 | doi = 10.1074/jbc.M111.306340 | doi-access = free | url = }} The gene encoding MMP14 is organized into ten exons, with the novel C-terminal peptide domains and the 3'-untranslated region encoded by a single large exon; this structure is distinct from other MMP family members.{{cite journal | vauthors = Apte SS, Fukai N, Beier DR, Olsen BR | title = The matrix metalloproteinase-14 (MMP-14) gene is structurally distinct from other MMP genes and is co-expressed with the TIMP-2 gene during mouse embryogenesis | journal = The Journal of Biological Chemistry | volume = 272 | issue = 41 | pages = 25511–7 | date = October 1997 | pmid = 9325265 | doi = 10.1074/jbc.272.41.25511 | doi-access = free | url = }} The exons for the catalytic and pro-domains are unique to MMP14, while the hemopexin-like domains share similarity with other MMPs. The short intracellular domain (ICD) of MMP14 contains a unique lysine residue (Lys581) that can be mono-ubiquitinated, a modification that regulates the enzyme’s trafficking and cellular invasion functions. This structural arrangement allows MMP14 to localize its proteolytic activity to the pericellular environment, facilitating processes such as extracellular matrix remodeling, cell migration, and activation of other MMPs, notably pro-MMP2.

MMP14 (matrix metalloproteinase-14) is a membrane-anchored enzyme with critical roles in tissue remodeling, development, and cellular metabolism. Its primary function is the proteolytic degradation of extracellular matrix (ECM) components, which is essential for processes such as organ development, cell migration, and branching morphogenesis. MMP14 directly activates other MMPs, most notably MMP2, and indirectly activates MMP13 and MMP9, thereby amplifying ECM remodeling and facilitating cellular invasion, a mechanism particularly relevant in cancer metastasis. Beyond its catalytic activity, MMP14 interacts with cell surface molecules (such as CD44 and integrins) to modulate cell signaling and behavior. Studies in knockout mice have shown that loss of MMP14 leads to severe defects in collagen turnover, impaired adipogenesis, metabolic imbalance, and increased autophagy, highlighting its role in maintaining metabolic homeostasis and energy storage. MMP14 integrates extracellular matrix remodeling with intracellular energy regulation, making it an important regulator of both tissue structure and metabolic balance.{{cite journal | vauthors = Mori H, Bhat R, Bruni-Cardoso A, Chen EI, Jorgens DM, Coutinho K, Louie K, Bowen BB, Inman JL, Tecca V, Lee SJ, Becker-Weimann S, Northen T, Seiki M, Borowsky AD, Auer M, Bissell MJ | title = New insight into the role of MMP14 in metabolic balance | journal = PeerJ | volume = 4 | issue = | pages = e2142 | date = 2016 | pmid = 27478693 | pmc = 4950575 | doi = 10.7717/peerj.2142 | doi-access = free | url = }}

Increased expression of MMP14 has been observed in several cancers, including bladder, breast, colorectal, and renal cancers, and is often associated with more advanced disease and poorer short-term prognosis.{{cite journal | vauthors = Li M, Li S, Zhou L, Yang L, Wu X, Tang B, Xie S, Fang L, Zheng S, Hong T | title = Immune Infiltration of MMP14 in Pan Cancer and Its Prognostic Effect on Tumors | journal = Frontiers in Oncology | volume = 11 | issue = | pages = 717606 | date = 2021 | pmid = 34604053 | pmc = 8484967 | doi = 10.3389/fonc.2021.717606 | doi-access = free | url = }}{{cite journal | vauthors = Zhao YW, Ma W, Jiang F, Xie Y, Tang L | title = Upregulation of matrix metalloproteinase 14 (MMP14) is associated with poor prognosis in renal clear cell carcinoma-a bioinformatics analysis | journal = Translational Andrology and Urology | volume = 11 | issue = 11 | pages = 1523–1534 | date = November 2022 | pmid = 36507474 | pmc = 9732706 | doi = 10.21037/tau-22-619 | doi-access = free | url = }}{{cite journal | vauthors = Cui G, Cai F, Ding Z, Gao L | title = MMP14 predicts a poor prognosis in patients with colorectal cancer | journal = Human Pathology | volume = 83 | issue = | pages = 36–42 | date = January 2019 | pmid = 30120968 | doi = 10.1016/j.humpath.2018.03.030 | url = }}{{cite journal | vauthors = Wang JF, Gong YQ, He YH, Ying WW, Li XS, Zhou XF, Zhou LQ | title = High expression of MMP14 is associated with progression and poor short-term prognosis in muscle-invasive bladder cancer | journal = European Review for Medical and Pharmacological Sciences | volume = 24 | issue = 12 | pages = 6605–6615 | date = June 2020 | pmid = 32633349 | doi = 10.26355/eurrev_202006_21646 | url = }}{{cite journal | vauthors = Makutani Y, Kawakami H, Tsujikawa T, Yoshimura K, Chiba Y, Ito A, Kawamura J, Haratani K, Nakagawa K | title = Contribution of MMP14-expressing cancer-associated fibroblasts in the tumor immune microenvironment to progression of colorectal cancer | journal = Frontiers in Oncology | volume = 12 | issue = | pages = 956270 | date = 2022 | pmid = 36052235 | pmc = 9424903 | doi = 10.3389/fonc.2022.956270 | doi-access = free | url = }} High MMP14 expression in tumor tissues correlates with increased tumor progression, metastasis, and reduced survival rates, particularly in muscle-invasive bladder cancer and colorectal cancer. In addition, MMP14 is involved in the tumor microenvironment, including its expression by cancer-associated fibroblasts, which may contribute to tumor recurrence and resistance to certain chemotherapies. While these associations suggest that MMP14 could serve as a useful prognostic biomarker and potential therapeutic target, its precise role and clinical utility may vary depending on cancer type and context.

MMP14 has been shown to interact with TIMP2.{{cite journal | vauthors = Zucker S, Drews M, Conner C, Foda HD, DeClerck YA, Langley KE, Bahou WF, Docherty AJ, Cao J | title = Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP) | journal = Journal of Biological Chemistry | volume = 273 | issue = 2 | pages = 1216–1222 | date = Jan 1998 | pmid = 9422789 | doi = 10.1074/jbc.273.2.1216 | doi-access = free }}

• Matrix metalloproteinase
• ARK5

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• {{cite journal | vauthors = Nagase H, Woessner JF | title = Matrix metalloproteinases. | journal = Journal of Biological Chemistry | volume = 274 | issue = 31 | pages = 21491–21494 | date = Jul 1999 | pmid = 10419448 | doi = 10.1074/jbc.274.31.21491 | doi-access = free }}

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• The MEROPS online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=M10.014 M10.014]

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Category:Matrix metalloproteinases

Category:EC 3.4.24

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