MMP-1

Official Full Name

matrix metallopeptidase 1

Organism

Homo sapiens

GeneID

4312

Background

This gene encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. The encoded preproprotein is proteolytically processed to generate the mature protease. This secreted protease breaks down the interstitial collagens, including types I, II, and III. The gene is part of a cluster of MMP genes on chromosome 11. Mutations in this gene are associated with chronic obstructive pulmonary disease (COPD). Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

Synonyms

CLG; CLGN;

Bio Chemical Class

Peptidase

Protein Sequence

MHSFPPLLLLLFWGVVSHSFPATLETQEQDVDLVQKYLEKYYNLKNDGRQVEKRRNSGPVVEKLKQMQEFFGLKVTGKPDAETLKVMKQPRCGVPDVAQFVLTEGNPRWEQTHLTYRIENYTPDLPRADVDHAIEKAFQLWSNVTPLTFTKVSEGQADIMISFVRGDHRDNSPFDGPGGNLAHAFQPGPGIGGDAHFDEDERWTNNFREYNLHRVAAHELGHSLGLSHSTDIGALMYPSYTFSGDVQLAQDDIDGIQAIYGRSQNPVQPIGPQTPKACDSKLTFDAITTIRGEVMFFKDRFYMRTNPFYPEVELNFISVFWPQLPNGLEAAYEFADRDEVRFFKGNKYWAVQGQNVLHGYPKDIYSSFGFPRTVKHIDAALSEENTGKTYFFVANKYWRYDEYKRSMDPGYPKMIAHDFPGIGHKVDAVFMKDGFFYFFHGTRQYKFDPKTKRILTLQKANSWFNCRKN

Open

Disease

Brain cancer, Chronic kidney disease, Corneal disease, Hepatitis virus infection, Kaposi sarcoma, Lung cancer, Multiple sclerosis, Pancreatic cancer, Prostate cancer, Rheumatoid arthritis, Solid tumour/cancer

Approved Drug

1 +

Clinical Trial Drug

3 +

Discontinued Drug

10 +

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Detailed Information

Matrix metalloproteinases (MMPs) is a family of proteases. Its remarkable feature is the structure of the hydrolysis-free matrix. MMP-1 is a member of the matrix metalloproteinase family and belongs to the collagen degrading enzyme. Its molecule is mainly composed of the hemoglobin-binding domain and the catalytic domain. The two domains are joined by a linker domain and exhibit complex conformational movements that bind to the matrix and undergo chemical reactions such as hydrolysis of collagen. MMP-1 is one of the most widely expressed matrix metalloproteinases and can degrade Class I, II and III collagen.

MMP-1 Function

MMP-1 has multiple functions for different substrates. MMP-1 can degrade some matrix molecules such as aggrecan, pluripotent glycans, basal proteoglycans, casein, nestin, serine protein inhibitors and mucin-C. Therefore, MMP-1 plays a key role in the physiological repair of the extracellular matrix (ECM) of the extracellular matrix. MMP-1 releases the bioactive molecules stored in the ECM by decomposition to function. Studies have shown that cell-matrix interactions, especially in contact with type I collagen, play a key role in exciting keratinocyte MMP-1 synthesis. Regulation of intracellular calcium blocks the secretion of MMP-1 from keratinocytes that are detached from the basal layer. When re-epithelization is complete, the basal keratinocytes stop expressing MMP-1.

MMP-1 Figure 1. CT-1 induces MMP-1 gene and protein expression as a source of proteolytic potential via MAP kinase (MAPK) pathway and JAK/STAT cascade in HAECs.( Tokito, A. , et al. 2013)

MMP-1 and Skin Aging

When MMP-1 is overexpressed in the body, it degrades the collagen of ECM, and the structure of the dermis is destroyed by the decomposition of collagen. The change in the structure of the dermis is the main cause of skin aging, and the thickness of the dermis of the aging skin is thinner and the density is lowered. After 20 years of age, the number of dermal fibroblasts gradually decreases, and the total collagen content decreases annually. Collagen synthesis of type III is reduced in aging skin. When skin ages, collagen stress transmission decreases and shear resistance decreases. MMP-1 is the most important enzyme for the degradation of type I and type III collagen. When MMP-1 is overexpressed, it specifically degrades the extracellular matrix components, breaking the normal structure of collagen fibers and elastic fibers, so MMP-1 causes skin to appear. The most important enzyme for aging symptoms such as wrinkle and fine lines, together with TIMP-1, maintains the dermis structure.

MMP-1 and Tumor

Many clinical studies have shown that increased expression of MMP-1 is associated with the incidence and aggressiveness of many types of tumors, including rectal cancer, esophageal cancer, gastric cancer, breast cancer, and malignant melanoma. In addition, elevated levels of MMP-1 expression in atypical ductal hyperplasia can be used as markers to predict which patients develop invasive breast cancer. Studies suggest that up-regulation of MMP-1 is associated with poor prognosis in breast cancer. MMP-1 can promote tumor metastasis by activating the G protein-coupled receptor PAR1 and releasing signaling precursors such as pro-TGFα, pro- TGFβ. This signaling pathway drives autocrine and paracrine signals in tissues, enabling MMP-1 promotes angiogenesis and activation of osteoclasts.

Breast cancer cells secrete MMP-1, disrupting the barrier of the cerebral vascular endothelium and increasing the permeability of the blood-brain barrier (BBB). Cerebral vascular endothelial cells infiltrated by tumor cells can help cancer cells enter the central nervous system and proliferate in the brain. The study found that of all matrix metalloproteinases, only MMP1 was significantly up-regulated in brain metastatic cell lines. MMP1 is strongly expressed in both primary and brain metastases. In patients with only primary lesions without brain metastasis, the gene expression was weak. These results suggest that MMP-1 plays an important role in brain metastasis of breast cancer.

References:

Singh, W., Fields, G. B., Christov, C. Z., & Karabencheva-Christova, T. G. (2016). Effects of mutations on structure–function relationships of matrix metalloproteinase-1. International Journal of Molecular Sciences, 17(10), 1727.
Chiranjeevi, P. , Aiyengar, T. M. , Kaushik, P. , Srilatha, G. , Nivas, S. , & Spurthi, K. M. , et al. (2017). Synergistic effect of collagenase-1 (mmp1), stromelysin-1 (mmp3) and gelatinase-b (mmp9) gene polymorphisms in breast cancer. PLOS ONE, 12 (9), e0184448.
Tokito, A. , Jougasaki, M. , Ichiki, T. , & Hamasaki, S. . (2013). Cardiotrophin-1 induces matrix metalloproteinase-1 in human aortic endothelial cells. PLOS ONE, 8(7), e68801.

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