As implied above, the structure of organisms and their tissues depends on the adhesion and inter- action of cells to each other as well as of cells to basement membranes and the ECM. The cad- herins are the major mediators of cell-cell adhesion, while the integrins mediate the attachment of cells to basement membranes and the ECM. Both the adherens junctions and the focal adhe- sions involve an intracellular interaction between the cytoplasmic portion of the adhesion mole- cule, cadherin or integrin, with cytoskeletal components (Chapter 16) and signal transduction pathways (Chapter 7). Figure 10.5 presents diagrammatic and hypothetical illustrations of an adherens junction and focal adhesions with their extracellular contacts and intracellular associa- tions with protein species. The adherens junction diagrams the interaction or “zipper” intercellu- lar contact zone between molecules of cadherens on one cell and those on another. Such interactions involve two dimers interacting in an antiparallel orientation through their adhesive binding surfaces, thus forming a continuous linear ribbon structure (Gumbiner, 1996; Aberle et al., 1996). These interactions also involve calcium-binding pockets that bridge and stabilize the successive structural repeats through coordination of acidic amino acid residues and align the domains into a rod shape (cf. Aberle et al., 1996). The cytoplasmic domains of the cadherins interact with catenins α and β and plakoglobin, which is closely related to β-catenin. These mol- ecules, in turn, interact with the cytoskeleton, directly or indirectly—both microfilaments and intermediate filaments (Chapter 16). In addition, the catenins may complex with the product of the tumor suppressor gene, APC or adenomatous polyposis coli (Chapter 5; Polakis, 1997; Aberle et al., 1996). Certain functional ratios of cadherins, catenins, and the APC gene product seem to be necessary for the maintenance of a normal phenotype in epithelial cells (cf. Rosales et al., 1995). These complexes and/or another protein, p120cas, are involved in protein phos-
Figure 10.5 (A) A model illustration of the adherins junction showing the interaction of cadherins from two different cells. Each cadherin is associated through its intracellular component with the proteins α, α- catenin; β, β-catenin; p, plakoglobin (adapted from Takeichi et al., 1993, with permission of authors and publisher). (B) Focal adhesion assembly models showing on the left a quiescent cell adhering to the extra- cellular matrix (ECM). Interactions of integrins binding to the ECM in the extracellular component are noted. The integrins are linked to the cytoskeleton via proteins such as talin and others which are not shown. In the left portion of the figure integrins are shown under little tension with the myosin in a relaxed conformation. In the right-hand portion of the figure is seen myosin light chain phosphorylation stimulated in response to Rho (a member of the G protein family) activation. Myosin is shown as assembling into bipolar filaments generating tension on actin, resulting in clustering of the integrins bound to the ECM. This integrin clustering activates the focal adhesion kinase (FAK) leading to autophosphorylation (FAK- PY) and recruitment of other members of the signaling complex noted as a star. The model depicted is not meant to demonstrate all components of the assembly, but rather those of greater importance. (Adapted from Burridge et al., 1997, with permission of the authors and publisher.)
phorylation by cellular tyrosine kinases. Thus, catenin complexes appear to be involved in signal transduction pathways, but the exact mechanisms for this are not clear as yet. Takeichi et al. (1993) suggested that tyrosine phosphorylation of β-catenins may modulate their actions so as to loosen cell-cell contacts, causing a destabilization of the cadherin-cadherin interactions.
Focal adhesions (Figure 10.5) involve an interaction of cells with basement membranes and the ECM mediated by plasma membrane–spanning integrins. The cytoplasmic portion of the β integrin interacts with intracellular proteins such as talin and vinculin, as noted in the figure, which, in turn, associate with actin molecules of the microfilaments. In the figure, it is hypothe- sized that intracellular alterations leading to microfilament contraction cause a clustering of the integrin dimers, producing and strengthening focal adhesions and their interaction with the ECM and/or basement membranes (Figure 10.5). Also noted in the figure is the mediator of signal transduction, the focal adhesion kinase (FAK) (Burridge et al., 1997). This kinase interacts di- rectly with the cytoplasmic tail of the β integrin subunit and also contains at least two SH2 bind- ing domains (Chapter 7). It has been suggested (Clark and Brugge, 1995) that clustering of the integrins activates FAK, which in turn induces its autophosphorylation and subsequent binding to SH2 domains of signal transduction molecules such as Src and Grb2. A small GTP-binding protein, rho, appears to regulate the assembly of focal adhesions with actin fibers in response to growth factors (Ridley and Hall, 1992). This pathway may then continue the signal through ras to MAPK and the nucleus (Chapter 7). Thus, by alterations from the environment or from within the cell, adhesion molecules and the adhesive interaction of cells with each other and with the ECM and basement membranes can lead to dramatic alterations in gene expression within cells during normal development, hormonal alterations within the organism, or reaction to noxious external stimuli. Alterations in cell adhesion play a major role in the biological activity of neo- plastic cells that invade and metastasize during the stage of progression.