Cell Substratum Interactions

There are a number of mechanisms that control how a cell perceives and responds to the ECM. These include integrin-ligand interactions, influences of surface chemistry, and the topographical effects of the matrix itself. Undoubtedly, all of these factors come into play to influence the community of intracellular proteins that, in turn, dictate cell behavior.

Integrins are a family of transmembrane glycoproteins that are composed of two subunits, a and b, which are covalently bound together. The ab heterodimer determines the specificity for ligands found in proteins located in the ECM. These ligands are amino acid sequences with the RGD sequence binding the largest number of integrin receptors. ECM-associated integrin-binding sequences include RGDS, LDV, and REDV sequences of fibronectin that bind a5b1 and RGDV of vitronectin that binds avb3. By linking the actin cytoskeleton to the ECM, integrins provide bidirectional transmission of signals between the ECM and cytoplasm. This linkage occurs at sites of focal adhesions. Several proteins have been found to be concentrated around these sites and act as linking elements, including cytoplasmic proteins such as vinculin, talin, and a-actinin. Integrins participate in cell signaling by undergoing activation and deactivation as a result of ligand binding. Activation results in conformational changes in integrin extracellular domains, reorganization of intracytoplasmic connections, and redistribution of integrins on the cell surface. This redistribution of receptors leads to a series of events inside the cell, including changes in pH and calcium, tyrosine phosphorylation of proteins such as focal adhesion kinase (FAK), and activation of the RAS-ERK cascade. It is believed that providing stable cell attachment conditions, integrins also allow for growth factor receptors to be optimally activated. Integrin activation is also important for normal cell cycle function and the extension of lamellipodia, filiopodia, and stress fiber formation during cell movement (1-6).

The cytoskeleton of a cell also participates in mediating responses to the ECM through interactions with integrin receptors at sites of focal adhesions. The cytoskeleton is composed of three different types of molecular proteins known as microfilaments (actin), microtubules (tubulin), and intermediate filaments (keratin). Microfilaments range in diameter from 7 mm to 9 mm; microtubules average 24 mm, and intermediate filaments average 10 mm (7). The cytoskeleton not only provides mechanical support but also is directly involved in a large number of signaling pathways often in association with G proteins. Through these pathways, transduction of external forces through the cytoskeleton can induce phosphorylation of tyrosine kinases, recruitment of phospholipases and lipid kinases to the cytoskeleton, regulation of intracellular Ca2 + and transmembrane ion flux, and control of nuclear gene expression (8-10).

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