Cell-cell adhesion is fundamental to the organization and survival of multicellular organisms. Cell adhesion is mediated by specific transmembrane proteins or receptors exposed on the cell surface. These receptors transmit signals into the cell in response to the cellular environment to regulate cellular behavior. Cells also transmit internal signals to the adhesion receptors to regulate or alter receptor function. Alterations in the function, expression or signaling through adhesion receptors contribute to major diseases such as heart disease and cancer. Thus, it is important to understand how these receptors receive and transmit cellular signals. In this laboratory, we are studying adhesion receptors and signaling in the contexts of heart disease, which involves the study of platelets, cancer, which involves breast epithelial cells, and sickle cell disease, which involves sickle red blood cells and endothelial cells. In each case we are mapping signal transduction pathways sent to and via adhesion receptors. The types of adhesion receptors that we study most often are called integrins, which are present on most cell types. Techniques used include an array of molecular and biochemical approaches. For example, we are using the yeast two-hybrid system to identify proteins and protein motifs that bind to cytoplasmic domains of integrins. Using this approach, we have identified a number of novel proteins potentially involved in integrin signaling that we are now in the process of characterizing. We have also identified novel signaling pathways in platelets, sickle cells and breast epithelial cells. To gain functional information, we express native and mutant proteins in cells, construct chimeras, and are initiating mouse knock-out and knock-in studies. We also use an extensive array of protein biochemical and biophysical approaches to characterize relevant proteins.