The interface between the plasma membrane and the cytoplasm of cells is the site for transfer of important information between extracellular and intracellular processes in functions as diverse as adhesion and tissue formation, cell and tissue movements, and the regulation of gene expression, cell growth, and the cytoskeleton. Coordination and spatial organization of cellular structures associated with this interface, such as adhesion sites, the intracellular actin-based cytoskeleton, and signal transduction systems, are thought to be crucial for key steps in embryonic development, wound healing, and differentiated tissue function. Integrins are the major class of receptors used by cells to interact with the extracellular matrix, and they mediate cell adhesion and transmembrane signaling from extracellular matrix molecules to the interior of cells. The roles of integrin cytoplasmic domains and several of the molecules that interact with integrins are being explored using molecular biology and biochemical methods. Functions of isolated domains and of individual cytoplasmic molecules are being tested using chimeric receptors containing a reporter domain consisting of a subunit of the interleukin-2 receptor and various molecules. A hierarchy of cytoplasmic responses was identified by analyses of the requirements for controlling the localization of specific molecules. Distinct roles were found for aggregation of integrins with or without ligand occupancy, intracellular tyrosine phosphorylation, and actin-based cytoskeletal integrity. Signaling molecule aggregation and signal transduction via the MAP kinase pathway formed another subset of these responses, and molecular mechanisms for integrin-growth factor synergism could be identified. Chimeras containing individual cytoskeletal and signal transduction molecules are being tested as mediators of steps in this hierarchy of responses. Characterization of these distinct biological steps provides novel tools for understanding the transmembrane spatial control of adhesion/signaling complexes that are essential for coordinating the complex rearrangements and final organization of oral, facial, and other developing tissues. These interactions are also likely to be important for adult tissue repair.
