Cells make extracellular matrix, organize it, and degrade it. The matrix in its turn exerts powerful influences on the cells. The influences are exerted chiefly through transmembrane cell adhesion proteins that act as matrix receptors. These proteins tie the matrix outside the cell to the cytoskeleton inside it, but their role goes far beyond simple passive mechanical attachment. Through them, components of the matrix can affect almost any aspect of a cell’s behavior. The matrix receptors have a crucial role in epithelial cells, mediating their interactions with the basal lamina beneath them. They are no less important in connective-tissue cells, mediating the cells’ interactions with the matrix that surrounds them.
Several types of molecules can function as matrix receptors or co-receptors, including the transmembrane proteoglycans. But the principal receptors on animal cells for binding most extracellular matrix proteins are the integrins. Like the cadherins and the key components of the basal lamina, integrins are part of the fundamental architectural toolkit that is characteristic of multicellular animals. The members of this large family of homologous transmembrane adhesion molecules have a remarkable ability to transmit signals in both directions across the plasma membrane. The binding of a matrix component to an integrin can send a message into the interior of the cell, and conditions in the cell interior can send a signal outward to control binding of the integrin to the matrix. Tension applied to an integrin can cause it to tighten its grip on intracellular and extracellular structures, and loss of tension can loosen its hold, so that molecular signaling complexes fall apart on either side of the membrane. In this way, integrins can serve not only to transmit mechanical and molecular signals, but also to convert one type of signal into the other.
Integrins are transmembrane heterodimers that Link the Extracellular Matrix to the Cytoskeleton
There are many varieties of integrins, but they all conform to a common plan. An integrin molecule is composed of two noncovalently associated glycoprotein subunits called α and β. Both subunits span the cell membrane, with short intracellular C-terminal tails and large N-terminal extracellular domains (Figure 19–55). The extracellular domains bind to specific amino acid sequence motifs in extracellular matrix proteins or, in some cases, in proteins on the surfaces of other cells. The best-understood binding site for integrins is the RGD sequence mentioned earlier (see Figure 19–47), which is found in fibronectin and other extracellular matrix proteins. Some integrins bind a Leu-Asp-Val (LDV) sequence in fibronectin and other proteins. Additional integrin-binding sequences, as yet poorly defined, exist in laminins and collagens.
Humans contain 24 types of integrins, formed from the products of 8 different β-chain genes and 18 different α-chain genes, dimerized in different combinations. Each integrin dimer has distinctive properties and functions. Moreover, because the same integrin molecule in different cell types can have different ligand-binding specificities, it seems that additional cell-type-specific factors can interact with integrins to modulate their binding activity. The binding of integrins to their matrix ligands is also affected by the concentration of Ca2+ and Mg2+ in the extracellular medium, reflecting the presence of divalent cation-binding domains in the α and β subunits. The divalent cations can influence both the affinity and the specificity of the binding of an integrin to its extracellular ligands.