Figure 19–54 Regeneration experiments demonstrating the special character of the junctional basal lamina at a neuromuscular junction. If a frog muscle and its motor nerve are destroyed, the basal lamina around each muscle cell remains intact and the sites of the old neuromuscular junctions are still recognizable. When the nerve, but not the muscle, is allowed to regenerate (upper right), the junctional basal lamina directs the regenerating nerve to the original synaptic site. When the muscle, but not the nerve, is allowed to regenerate (lower right), the junctional basal lamina causes newly made acetylcholine receptors (blue) to accumulate at the original synaptic site. these experiments show that the junctional basal lamina controls the localization of synaptic components on both sides of the lamina. Some of the molecules responsible for these effects have been identified. Motor neuron axons, for example, deposit agrin in the junctional basal lamina, where it regulates the assembly of acetylcholine receptors and other proteins in the junctional plasma membrane of the muscle cell. reciprocally, muscle cells deposit a particular isoform of laminin in the junctional basal lamina, and this molecule is likely to interact with specific ion channels on the presynaptic membrane of the neuron.
proteases cooperate to degrade matrix proteins such as collagen, laminin, and fibronectin. Some metalloproteases, such as the collagenases, are highly specific, cleaving particular proteins at a small number of sites. In this way, the structural integrity of the matrix is largely retained, while the limited amount of proteolysis that occurs is sufficient for cell migration. Other metalloproteases may be less specific, but, because they are anchored to the plasma membrane, they can act just where they are needed; it is this type of matrix metalloprotease that is crucial for a cell’s ability to divide when embedded in matrix.
Clearly, the activities of the proteases that degrade the matrix must be tightly controlled, if the fabric of the body is not to collapse in a heap. Numerous mechanisms are therefore employed to ensure that matrix proteases are activated only at the correct time and place. Protease activity is generally confined to the cell surface by specific anchoring proteins, by membrane-associated activators, and by the production of specific protease inhibitors in regions where protease activity is not needed.
Matrix proteoglycans and Glycoproteins regulate the activities of Secreted proteins
The physical properties of extracellular matrix are important for its fundamental roles as a scaffold for tissue structure and as a substrate for cell anchorage and migration. The matrix also has an important impact on cell signaling. Cells communicate with each other by secreting signal molecules that diffuse through the extracellular fluid to influence other cells (discussed in Chapter 15). En route to their targets, the signal molecules encounter the tightly woven meshwork of the extracellular matrix, which contains a high density of negative charges and protein-interaction domains that can interact with the signal molecules, thereby altering their function in a variety of ways.
The highly charged heparan sulfate chains of proteoglycans, for example, interact with numerous secreted signal molecules, including fibroblast growth factors (FGFs) and vascular endothelial growth factor (VEGF), which (among other effects) stimulate a variety of cell types to proliferate. By providing a dense array of growth factor binding sites, proteoglycans are thought to generate large local reservoirs of these factors, limiting their diffusion and focusing their actions on nearby cells. Similarly, proteoglycans might help generate steep growth factor gradients in an embryo, which can be important in the patterning of tissues during development. FGF activity can also be enhanced by proteoglycans, which oligomerize the FGF molecules, enabling them to cross-link and activate their cell-surface receptors more effectively.