The importance of proteoglycans as regulators of the distribution and activity of signal molecules is illustrated by the severe developmental defects that can occur when specific proteoglycans are inactivated by mutation. In Drosophila, for example, the function of several signal proteins during development is governed by interactions with the membrane-associated proteoglycans Dally and Dally-like. These members of the glypican family are thought to concentrate signal proteins in specific locations and act as co-receptors that collaborate with the conventional cell-surface receptor proteins; as a result, they promote signaling in the correct location and prevent it in the wrong locations. In the Drosophila ovary, for example, Dally is partly responsible for the restricted localization and function of a signaling protein called Dpp, which blocks differentiation of the germ-line stem cells: when the gene encoding Dally is mutated, Dpp activity is greatly reduced and oocyte development is abnormal.
Several matrix proteins also interact with signal proteins. The type IV collagen of basal laminae interacts with Dpp in Drosophila, for example. Fibronectin contains a type III fibronectin repeat that interacts with VEGF, and another domain that interacts with another growth factor called hepatocyte growth factor (HGF), thereby promoting the activities of these factors. As discussed earlier, many matrix glycoproteins contain extensive arrays of binding domains, and the arrangement of these domains is likely to influence the presentation of signal proteins to their target cells (see Figure 19–46).
Finally, many matrix glycoproteins contain domains that bind directly to specific cell-surface receptors, thereby generating signals that influence the behavior of the cells, as we describe in the next section.
Cells are embedded in an intricate extracellular matrix, which not only binds the cells together but also influences their survival, development, shape, polarity, and migratory behavior. The matrix contains various protein fibers interwoven in a network of glycosaminoglycan (GAG) chains. GAGs are negatively charged polysaccharide chains that (except for hyaluronan) are covalently linked to protein to form proteoglycan molecules. GAGs attract water and occupy a large volume of extracellular space. Proteoglycans are also found on the surface of cells, where they often function as co-receptors to help cells respond to secreted signal proteins. Fiber-forming proteins give the matrix strength and resilience. The fibrillar collagens (types I, II, III, V, and XI) are ropelike, triple-stranded helical molecules that aggregate into long fibrils in the extracellular space, thereby providing tensile strength. They also form structures to which cells can be anchored, often via large multidomain glycoproteins, such as laminin and fibronectin, that bind to integrins on the cell surface. Elasticity is provided by elastin molecules, which form an extensive cross-linked network of fibers and sheets that can stretch and recoil.
The basal lamina is a specialized form of extracellular matrix that underlies epithelial cells or is wrapped around certain other cell types, such as muscle cells. Basal laminae are organized on a framework of laminin molecules, which are linked together by their side-arms and bind to integrins and other receptors in the basal plasma membrane of overlying epithelial cells. Type IV collagen molecules, together with the protein nidogen and the large heparan sulfate proteoglycan perlecan, assemble into a sheetlike mesh that is an essential component of all mature basal laminae. Basal laminae provide mechanical support for epithelia; they form the interface and attachment between epithelia and connective tissue; they serve as filters in the kidney; they act as barriers to keep cells in their proper compartments; they influence cell polarity and cell differentiation; and they guide cell migration during development and tissue regeneration.