Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

THE EXTRACELLULAR MatrIX OF ANIMALS
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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.
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 germline
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).