More than 60 previously undetected SAM domain-containing proteins have been identified using profile searching methods. Among these are over 40 EPH-related receptor tyrosine kinases (RPTK), Drosophila bicaudal-C, a p53 from Loligo forbesi, and diacyglycerol-kinase isoform delta. This extended dataset suggests that SAM is an evolutionary conserved protein binding domain that is involved in the regulation of numerous developmental processes among diverse eukaryotes. A conserved tyrosine in the SAM sequences of the EPH related RPTKs is likely to mediate cell-cell initiated signal transduction via the binding of SH2 containing proteins to phosphotyrosine.