The cell. 2.Extracellular matrix
Glycoproteins are key molecules for the cohesion of tissues.
Fibronectin binds extracellular molecules such as collagen, proteoglycans, fibrin, as well as cell surface receptors.
Tenascin binds proteoglycans as well as integrins and other cell membrane receptors.
Laminin is a main component of the basal lamina.
Metalloproteinases and serine proteases are necessary for remodeling and recycling the extracellular matrix.
Cells are attached to the extracellular matrix, which is a network of molecules linked to each other. Most of the linkages between molecules in the extracellular matrix are based on protein-protein interactions, but protein-carbohydrate adhesions also help to strengthen the molecular network. There are three adhesion mechanisms to maintain the structural integrity of tissues: cell-cell adhesions, cell-extracellular matrix adhesions, and linkages between molecules of the extracellular matrix. Here, we will deal with the first one, whereas we will learn about the other two mechanisms in the cell membrane page because these adhesions dependens on transmembrane proteins.
Glycoproteins greatly contribute to make the extracellular matrix a cohesive network of molecules, although they also perform other functions. Glycoproteins are intermediaries that link structural molecules between each other, and also link structural molecules and cells. In each glycoprotein molecule, there are several domains binding different molecules that altogether forms cross-linked molecular networks. Fibronectins, laminins and tenascins are major glycoproteins of the extracelular matrix of animals.
Drawing of a fibronectin molecule. It is composed of two amino acid chains joined together by disulfide bridges close to the carboxyl terminal residue. Molecular domains that interact with and join to other molecules are indicated (modified from Pankov and Yamada, 2002).
Fibronectins are glycoproteins consisting of two polypeptides joined by disulfide bridges. They have several molecular domains that recognize and bind to glycosaminoglycans, proteoglycans, fibrin, heparin and some transmembrane proteins such as integrins. Therefore, fibronectins are intermediaries that make connections between different extracellular matrix molecules, but also between extracellular matrix and cells. They are one of the most important molecules responsible for extracellular matrix consistence. Fibronectins are found in almost every tissue. They can be found as insoluble fibers in connective tissues, or soluble molecules in body fluids such as blood. Besides maintaining extracellular matrix cohesion, fibronectins have many other functions. For example, during embryonic development, cells move from one side to another through adhesion paths made of fibronectin. They are also important during tissue remodeling.
Drawing of a laminin molecule. It consists of three amino acid chains. The molecular domains for interaction (adhesion) with other molecules of the extracelular matrix and of the cell surface are indicated (modified from Mouw et al:, 2004).
Laminin is a major component of the basal lamina. It consists of three highly glycosylated polypeptides: alpha, beta and gamma, joined together by disulfide bridges. There are 5 types of alpha chains, 3 of beta chains, and 3 of gamma chains, that are combined to form different types of laminins, although not all combinations may be possible because only 16 laminin subtypes have been found in humans. Laminin is synthesized by epithelial cells, muscle cells, neurons, and bone marrow cells. Epithelial and muscle cells release laminin to the basal lamina, which is a sheet of extracellular matrix that separates these cells from connective tissue. Besides the structural function in the extracelular matrix, laminin also influences cell behavior and differentiation through interactions with integrins. That is why mutation of laminins usually leads to pathological processes. During embryonary development, laminin is the first type of glycoprotein to be released to the extracellular matrix.
Tenascin forms a family of large size proteins that can bind between each other, and are found in several types of tissues, including embryonic tissues, wounds, and tumors. They are able to bind to cell membrane proteins such as integrins, immunoglobulin receptors, proteoglycans, and annexin II. Tenascin also interacts with other proteins of the extracellular matrix such as fibronectin and certain proteoglycans.
Matricellular glycoproteins. Around the nineties of the XX century, it was observed that some glycoproteins of the extracellular matrix do not increase but decrease the adhesion strength of cells. Furthermore, knockout of these proteins appears not to have any impact on animal physiology. These proteins have domains for binding collagen, fibronectin and some cell receptors, but their main function is not to keep structural integrity of the extracellular matrix. They are released into the extracellular matrix during particular periods of time and in specific places by many types of cells. Although they can make adhesion contacts with other molecules, these glycoproteins decrease the adhesion of cells to several extracellular matrix components, are always present in tissue under remodeling processes, and are very abundant in the extracellular matrix of embryos. Therefore, they are not constitutive but temporary proteins in the extracellular matrix.
One major function of matricellular proteins is modifying the cell activity and facilitating the extracellular matrix remodeling. These processes take place during the embryonary period, in normal tissue development, and during tissue repairing after pathological damage. Some of these proteins influence the cell activity even before they are released to the extracellular matrix, i.e., in intracellular compartments. Tenascin, trompospondin, osteopontin, fibulin, and SPARC protein are matricellular proteins.
Drawing of a tenascin molecule. It is a modular structure with 6 repeated polypeptides connected between each other. Colors represent molecular domains.
Tenascins form a family of large molecular size glycoproteins located in the extracellular matrix of animals. The molecular structure shows a modular hexameric organization. Several isoforms of tenascin can be obtained by alternative splicing of the messenger RNA. Tenascin-C was the first tenascin isoform discovered. It is released into the extracellular matrix of tendons, bones and cartilage during the embryonary development. However, it can be also found in other tissues. Although it is very scarce in adult tissues, tenascin-C is overexpressed as a consequence of tissue damages like heart attack. Tenascin-R is abundant in the nervous system, both during development and in adults. Tenascin-X is present in the connective tissue and can be abundant in muscles under heavy activity, like in professional athletes. Teanscin-Y and -W have also been described. Tenascin-Y is homologous to avian tenascin-X. Like other glycoproteins, tenascins change the cohesive state of the extracellular matrix by binding integrins, fibronectins, collagens and proteoglycans. In animals, each type of tenascin is expressed in particular locations of the organism, that may change during development. The expression of tenascins is induced in tissues being repaired, or during tumor and pathological processes.
Osteopontin is found in bones, where it is involved in mineralization and remodeling, and in kidneys. Lower amount is also present in cartilage.
Fibulins form a group of 7 glycoproteins associated to the basal lamina, elastic fibers and other components of the extracellular matrix. Each of the 7 members shows a differential expression in different tissues and during development. Fibulin 5 is important for elastic fibers because it can bind tropoelastin. Besides the influence in the extracellular matrix network, fibulins modulate the cell behavior, so that these molecules work as matricelular and structural proteins.
Extracellular matrix turnover: metalloproteinases
Extracellular matrix of animals is in constant turnover by a process of degradation and synthesis of molecules, which are under the control of the cell. Degradation is carried out by metalloproteinase enzymes. They are associated with the external layer of plasma membrane as free molecules (previously secreted), or they may be inserted in the plasma membrane. In both cases the catalytic domain is extracellular. Metalloproteinases are synthesized as inactive forms, known as prometalloproteinases, and are activated by proteolytic cleavage, which is carried out by enzymes located in the plasma membrane. In mammals, there are more than 20 types of metalloproteinases, which degrade different types of extracellular matrix molecules. A type of metalloproteinase can degrade several types of molecules, but is mostly active on one type. Thus, there are collagenases, gelatinases, and some others, depending on their main substrate.
Besides maintaining the extracellular matrix homeostasis, metalloproteinases are key players in the extracellular matrix remodeling after certain signals, such as hormones, during pathological processes like inflammation, during repairing wounded tissues, in tumor metastasis, and during embryonic development. Another role of metalloproteinases is to release molecules that are retained by the extracellular matrix, which become free signals for neighbor cells. Metalloproteins are produced by fibroblasts, but also by epithelium, chondrocytes, osteoblasts, leukocytes, as well as by cancer cells.
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Updated: 2017-11-03. 20:43
Atlas of Plant and Animal Histology
Dep. of Functional Biology and Health Sciences.
Faculty of Biology.
University of Vigo