Proteins with SH2 domains: transducers in the tyrosine kinase signaling pathway.

SH22 domains are protein motifs consisting of approximately 100 amino acids which were originally described by Sadowski et a!. (1). This domain was discovered when the noncatalytic domains of cytoplasmic tyrosine kinases such as fps were compared to src (1) and subsequently described in the enzyme PLC-y (2, 3) and the oncogene v-ak (4). Interest in SH2 domains has heightened with the recent finding that these domains directly bind to protein sequences containing phosphotyrosmne (5). This finding, coupled with the fact that SH2 domains are found in molecules involved in growth factor mediated intracellular signaling and oncogenesis, indicates that SH2 domains are important in pathways utilized in growth control (6, 7). The focus of this review will be to discuss the general characteristics of 5H2 domains by reviewing several of the important SH2 domain containing proteins. In understanding the terminology of SH2 domains, it is instructive to examine the structure of src (Fig. 1 ). The tyrosine kinase domain of src represents src homology region 1, but this designation is not commonly utilized. Immediately amino-terminal to the tyrosine kinase domain lies the SH2 domain, which is designated in some other papers as the B and C box (3, 4). Next to the SH2 domain lies the SH3 domain, also known as the A box (3, 4). SH3 domains are approximately 50 amino acids long, and their function remains unknown, although they are found in cytoskeletal proteins such as spectnin (8). Proteins with SH2 domains often have accompanying SH3 domains (Fig. 1), and there is also a large group of proteins that have the SH3 domain only (5). Extensive comparisons of the amino acid sequence of SH2 domains have been published (5). Fig. 2 displays the amino acid sequence of a limited number of SH2 (Fig. 2A) and SH3 domains (Fig. 2B). Approximately 30 residues in SH2 domains are highly conserved, and three