Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Cell adhesion ECM remodeling

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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 andmetastasis. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes thatdegrade various components of the ECM in these processes. MMPs are divided into sixgroups, depending on their structure and substrate specificity: 1) Collagenases, such asMMP-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-1 (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. Thebalance between activated MMPs and TIMPs controls the extent of ECM remodeling [2], [3].

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

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

Stromelysin-2 is involved in the degradation of ECM proteins involved in woundrepair, 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 asMMP-14, MMP-15, and MMP-16 on the cell surface [9].

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

Plasminogen activator urokinase ( PLAU ) plays a pivotal role in the regulationof cell adhesion and migration during tissue remodeling. It activates intracellularsignaling upon binding to certain receptors on the cell surface. Kallikrein-relatedpeptidase 2 ( Kallikrein 2 ) can cleave PLAU to initiate its proteolyticcascade [14]. PLAU and Plasminogen activator tissue ( PLAT ) areimportant components of the extracellular protease system that specifically convertszymogen Plasminogen into Plasmin, the major fibrinolytic protease that ischaracterized by wide substrate specificity [15]. Plasmin directlydegrades ECM proteins, such as Fibronectin [16]. It alsoactivates a number of MMPs, including MMP-1 and MMP-13, that degrade theECM proteins and the components of the basal membrane, e.g., Collagen I,Collagen II, Collagen III, Collagen IV, andVitronectin [17], [18], [19], [20],[21], [22], [23], [24], [25],[26], [27], [28]. 

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

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

Kallikrein 2 and Kallikrein-related peptidase 3 ( Kallikrein 3 ) alsocleave Insulin-like growth factor binding protein 4 ( IBP4 ). IBP4fragments generated by kallikreins lose binding capacity to Insulin-like growth factors 1and 2 ( IGF-1 and IGF-2 ), thereby increasing bioavailability ofIGF-1 and IGF-2. The latter two activate IGF-1 receptor that isinvolved in the signaling implicated with cell growth, proliferation and survival [34], [12].

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

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

Cell surface heparan sulfate proteoglycans, CD44 and Syndecan-2, bind ECMchondroitin sulfate proteoglycan Versican and ECM protein Laminin, alpha 4 (LAMA4 ), respectively. CD44 and Syndecan-2 are implicated in theformation of a direct link between ECM and cortical cytoplasm via association with theactin 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; theseproteases can modify many non-matrix substrates, such as cytokines and chemokines. Forexample, MMP-9 potentiates Interleukin-8 ( IL-8 ) activity by aminoterminalprocessing. IL-8 signaling via Interleukin 8 receptor alpha ( IL8RA ) leadsto the activation of neutrophils and chemotaxis [52], [53].