Project Summary Receptor Tyrosine Kinases (RTKs) play profound and pervasive roles in biology and are associated with many different cancers, and are currently the focus of intense research. For practical reasons, most RTK studies are carried out in tissue culture which has both advantages and limitations. One limitation is that these studies do not examine RTKs in their native biological setting, and a deep understanding of how they perform their normal functions is often lacking. This application uses the developing Drosophila eye as a setting in which to study two distinctly different RTKs in their normal biological roles. One is the Drosophila EGF receptor (DER), which by structure and behavior is a standard RTK: it is a simple plasma membrane protein expressed ubiquitously at low levels, its ligand is a diffusible peptide, and its activation occurs on the plasma membrane. The other is Sevenless (Sev), an RTK with a number of unusual features. It has a multimeric structure, it is expressed at high levels and transduces a potent RTK signal, its ligand is an integral membrane protein, and its activation is linked to endocytosis which occurs in a cell-type specific manner. These features of Sev reflect its use by the developmental program to generate a high RTK signal in one specific photoreceptor precursor. Here we compare and contrast the structure and regulation of the two RTKs to understand how the unusual features of Sev allow it to perform its specific functions.