Exciting developments in biology often occur as a result of the discovery that a given protein plays a fundamental role in diverse aspects of cell function. One of the most dramatic examples has been the proteins implicated in the regulation of cell proliferation and the cell cycle. Recently, three areas of research that were evolving independently have converged in the discovery that a novel cytosolic tyrosine kinase with unique structural features may play a role in the action of oncogenic variants of pp60=, cell surface integrins, and mitogenic neuropeptides. The first area of research under consideration is the mechanism by which the src family of retroviral oncogenes causes malignant transformation. This has long proved elusive, mainly because of the difficulty in identifying substrates for the pp60” protein tyrosine kinase. One approach has been to generate monoclonal antibodies against individual proteins that are tyrosine phosphorylated in chicken embryo fibroblasts transformed by Rous sarcomavirus or expressing activated variants of src (Kanner et al., 1990). In this way, several potential substrates were identified, and the antibodies were subsequently used to clone the corresponding cDNAs from expression libraries. This approach yielded the unexpected result that one such substrate,~ 125, is itself a novel type of protein tyrosine kinase (Schaller et al., 1992). lmmunostaining of chicken embryo fibroblasts with antibodies to~ 125 (which in fact has a predicted molecular mass of 116 kd) shows that it colocalizes with several components of cellular focal adhesions, such as tensin, vinculin, and talin. Hence it has been termed~ 125~~~(focal adhesion kinase). What makes the deduced amino acid sequence of pl 25FAK interesting is the absence of noncatalytic motifs or domains found in other receptor and nonreceptor protein tyrosine kinases (Schaller et al., 1992). Thus, while pl 25FAK contains a central catalytic domain that exhibits all the conserved motifs characteristic of the catalytic domains of other protein tyrosine kinases, this region is flanked by