Behavior of cancer cells is profoundly affected by their microenvironment, which is often controlled by pericellular proteolysis or the processing of protein components, including extracellular matrices, growth factors, cytokines, receptors, cell adhesion molecules, and so on. Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteases responsible for the proteolytic events in the extracellular milieu. Among the multiple MMPs expressed in a wide range of tumors, membrane type-1 MMP (MT1-MMP), which is expressed especially in tumor cells with significant invasive properties, is thought to be particularly important for pericellular proteolysis. Recent studies have elucidated in part how MT1-MMP is regulated biologically for the promotion of invasion by tumors or for angiogenesis by endothelial cells. Understanding of the proteolysis by, and the regulation of MT1-MMP, which probably promotes cell invasion, could provide a therapeutic hint as to how to block or delay the progression of cancer.
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http://dx.doi.org/10.1111/j.1349-7006.2003.tb01484.x | DOI Listing |
Nat Commun
December 2024
Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
SPINT1, a membrane-anchored serine protease inhibitor, regulates cascades of pericellular proteolysis while its tissue-specific functions remain incompletely characterized. In this study, we generate Spint1-lacZ knock-in mice and observe Spint1 expression in embryonic pancreatic epithelium. Pancreas-specific Spint1 disruption significantly diminishes islet size and mass, causing glucose intolerance and downregulation of MAFA and insulin.
View Article and Find Full Text PDFJ Cell Biol
September 2024
Division of Genetic Medicine, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Dermal fibroblasts deposit type I collagen, the dominant extracellular matrix molecule found in skin, during early postnatal development. Coincident with this biosynthetic program, fibroblasts proteolytically remodel pericellular collagen fibrils by mobilizing the membrane-anchored matrix metalloproteinase, Mmp14. Unexpectedly, dermal fibroblasts in Mmp14-/- mice commit to a large-scale apoptotic program that leaves skin tissues replete with dying cells.
View Article and Find Full Text PDFActa Biomater
June 2024
Department of Orthopedic, Trauma, and Reconstructive Surgery, RWTH Aachen University Hospital, Pauwelsstraße 30, D-52074 Aachen, Germany.
The pericellular matrix (PCM) serves a critical role in signal transduction and mechanoprotection in chondrocytes. Osteoarthritis (OA) leads to a gradual deterioration of the cartilage, marked by a shift in the spatial arrangement of chondrocytes from initially isolated strands to large cell clusters in end-stage degeneration. These changes coincide with progressive enzymatic breakdown of the PCM.
View Article and Find Full Text PDFBioorg Med Chem
November 2023
Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, Via Torino 155, 30172 Venice, Italy; European Centre for Living Technology (ECLT), Ca' Bottacin, Dorsoduro 3911, Calle Crosera, 30123 Venice, Italy. Electronic address:
The inhibition of human urokinase-type plasminogen activator (huPA), a serine protease that plays an important role in pericellular proteolysis, is a promising strategy to decrease the invasive and metastatic activity of tumour cells. However, the generation of selective small molecule huPA inhibitors has proven to be challenging due to the high structural similarity of huPA to other paralogue serine proteases. Efforts to generate more specific therapies have led to the development of cyclic peptide-based inhibitors with much higher selectivity against huPA.
View Article and Find Full Text PDFMatrix Biol
May 2023
Laboratory of Tumor Microenvironment, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Stezzano 87, 24126 Bergamo, Italy. Electronic address:
Limited proteolysis of thrombospondins is a powerful mechanism to ensure dynamic tuning of their activities in the extracellular space. Thrombospondins are multifunctional matricellular proteins composed of multiple domains, each with a specific pattern of interactions with cell receptors, matrix components and soluble factors (growth factors, cytokines and proteases), thus with different effects on cell behavior and responses to changes in the microenvironment. Therefore, the proteolytic degradation of thrombospondins has multiple functional consequences, reflecting the local release of active fragments and isolated domains, exposure or disruption of active sequences, altered protein location, and changes in the composition and function of TSP-based pericellular interaction networks.
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