Cell adhesion - ECM remodeling

ECM remodeling

Extracellular matrix (ECM) remodeling is involved in normal physiological processes, such as embryonic development, reproduction, proliferation, cell motility and adhesion, wound healing, angiogenesis, as well as in disease processes, such as arthritis and metastasis. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade various components of the ECM in these processes. MMPs are divided into six groups, depending on their structure and substrate specificity: 1) Collagenases, such as MMP-1 and MMP-13, 2) Gelatinases, such as Gelatinase-A (MMP-2) and Gelatinase-B (MMP-9), 3) Stromelysins, such as Stromelysin-1 (MMP-3) and Stromelysin-2 (MMP-10), 4) Matrilysins, such as Matrilysin (MMP-7), 5) Membrane-type MMPs (MT-MMPs), such as the type-I transmembrane proteins MMP-14, MMP-15, and MMP-16,. 6) Other MMPs, such as MMP-12 [1].

Endogenous tissue inhibitors of metalloproteinases (TIMPs), such as TIMP1, TIMP2 and TIMP3, reduce excessive proteolytic ECM degradation by MMPs. The balance between activated MMPs and TIMPs controls the extent of ECM remodeling [2], [3].

MMPs are excreted by various connective tissues and pro-inflammatory cells including fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, and lymphocytes [4]. These enzymes are expressed as zymogens and are subsequently processed by other MMPs or other classes of proteolytic enzymes [1].

Stromelysin-1 activates a number of proMMPs, including the processing of MMP-1, MMP-13 and Matrilysin (MMP-7) into fully active proteinases [1]. Stromelysin-1 also degrades ECM proteins, e.g., Secreted protein acidic cysteine-rich (Osteonectin), as well as the components of basement membranes, such as Laminin 1 [5], [6], [7].

Stromelysin-2 is involved in the degradation of ECM proteins involved in wound repair, such as Collagen I, Collagen III, and Nidogen. Furthermore, it can activate other MMPs, such as MMP-1 [8].

MMP-2 is not activated by general proteinases, but by membrane MMPs, such as MMP-14, MMP-15, and MMP-16 on the cell surface [9].

Kallikrein serine protease 1 (Kallikrein 1) activates latent MMP-9 involved in the degradation of ECM proteins, such as Collagen I, Collagen II, Collagen III, Collagen IV, and Versican [10], [11], [12], [13].

Plasminogen activator urokinase (PLAU) plays a pivotal role in the regulation of cell adhesion and migration during tissue remodeling. It activates intracellular signaling upon binding to certain receptors on the cell surface. Kallikrein-related peptidase 2 (Kallikrein 2) can cleave PLAU to initiate its proteolytic cascade [14]. PLAU and Plasminogen activator tissue (PLAT) are important components of the extracellular protease system that specifically converts zymogen Plasminogen into Plasmin, the major fibrinolytic protease that is characterized by wide substrate specificity [15]. Plasmin directly degrades ECM proteins, such as Fibronectin [16]. It also activates a number of MMPs, including MMP-1 and MMP-13, that degrade the ECM proteins and the components of the basal membrane, e.g., Collagen I, Collagen II, Collagen III, Collagen IV, and Vitronectin [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28].

The proteolytic activity of Plasmin is regulated by plasminogen activator inhibitors, such as Serpin peptidase inhibitor (PAI1) and Serpin peptidase inhibitor member 2 (SERPINE2) that bind covalently to PLAU and PLAT and inhibit their catalytic activity [29], [30], [31], [32].

In addition to the proteolytic function, the tissue-type PLAU plays an important role in the cell migration and tissue remodeling. It binds to its receptor PLAUR and mediates a variety of functions involved in vascular homeostasis, inflammation and tissue repair [33].

Kallikrein 2 and Kallikrein-related peptidase 3 (Kallikrein 3) also cleave Insulin-like growth factor binding protein 4 (IBP4). IBP4 fragments generated by kallikreins lose binding capacity to Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), thereby increasing bioavailability of IGF-1 and IGF-2. The latter two activate IGF-1 receptor that is involved in the signaling implicated with cell growth, proliferation and survival [12], [34].

Cell surface heparan sulfate proteoglycan CD44 recruits proteolytically active Matrilysin (MMP-7) and precursor of Heparin-binding EGF-like growth factor (HB-EGF) to form a complex on the cell surface. Matrilysin (MMP-7) cleaves the membrane-bound HB-EGF precursor, thus releasing active HB-EGF. The latter then activates its receptors, Epidermal growth factor receptor (EGFR) and v-Erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4), thereby leading to cell proliferation, cell survival and tissue remodeling [35], [36].

ECM components regulate cell motility and adhesion in response to the external environmental processes, such as ECM remodeling [37]. For example, Collagen IV, the component of the basement membrane, binds to Alpha-1/beta-1 integrin. Fibronectin binds to Alpha-5/beta-1 integrin. This induces both cell adhesion, and intracellular signaling [38], [39], [40], [41], [42], [43], [44]. PLAUR binds to Alpha-5/beta-1 integrin and alters its conformation to promote ligand-binding affinity [45].

Cell surface heparan sulfate proteoglycans, CD44 and Syndecan-2, bind ECM chondroitin sulfate proteoglycan Versican and ECM protein Laminin, alpha 4 (LAMA4), respectively. CD44 and Syndecan-2 are implicated in the formation of a direct link between ECM and cortical cytoplasm via association with the actin cytoskeleton binding proteins Ezrin and Moesin [46], [47], [48], [49], [50], [51].

The action of MMPs is not restricted to degradation of the extracellular matrix; these proteases can modify many non-matrix substrates, such as cytokines and chemokines. For example, MMP-9 potentiates Interleukin-8 (IL-8) activity by aminoterminal processing. IL-8 signaling via Interleukin 8 receptor alpha (IL8RA) leads to the activation of neutrophils and chemotaxis [52], [53].

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