During development and growth of multicellular organisms the extracellular environment coordinates specification of particular differentiated cell fates with cell proliferation, survival, and morphological changes. The mechanisms by which cells sense and respond to the extracellular environment, and especially the features that distinguish distinct cellular responses, are fundamental to understanding cell and organ function in the normal organism and in pathology. Deficient cell survival is thought to underlie degenerative diseases and stroke. Deficient cell death, cell cycle regulation, and cellular properties such as invasiveness are thought to underlie initiation and progression of cancers. One class of related cell surface receptor proteins, the receptor tyrosine kinases (RTKs), play important roles in cell fate specification, survival, proliferation, motility and morphology. The fruit fly Drosophila melanogaster has proved useful for investigating receptor tyrosine kinase function, because its facile genetics permits the identification and analysis of specific protein functions in vivo. Such studies have identified many of the intracellular proteins that act during RTK-mediated cell fate specification in the retina, a tissue whose anatomy is particularly suited for developmental studies. A major goal is now to characterize the intracellular pathways of response to RTK signaling that regulate cell cycle progression, cell cycle arrest, survival and cell morphology. This will be achieved through genetic and molecular manipulation of RTK function in the developing retina. Such studies seek to reveal the in vivo roles of each ligand, receptor isoform, and intracellular signaling target for one particular RTK, the EGF receptor, and to identify those intracellular components that specify the particular type of response in each particular cell. Further studies will develop new reagents to focus on the molecular mechanisms of cell death and survival that are regulated by the EGFR. Together these studies will precisely dissect pathways of RTK function in vivo and identify those components that are specific for particular cellular responses important in human disease.
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