Interestingly, in Drosophila, awd has been shown to interact genetically with dynamin to promote endocytosis, although it is not yet clear which endocytic process is regulated by awd. In neurons, awd has been shown to promote Dynamin mediated neurotransmitter compound libraries uptake at the neuromuscular junction. Proper tracheal branching morphogenesis Inhibitors,Modulators,Libraries requires awd function to regulate internalization and signaling of the fibroblast growth factor receptor encoded by the breathless gene. During oogenesis awd is down regulated in border cells to allow for accumulation of and chemotactic signaling from the platelet derived growth fac tor vascular endothelial growth factor recep tor. Awd also regulates Domeless signaling via modulating endocytosis.

Moreover, loss of awd function in the follicular epithelium causes mislocalization of B catenin and DE cadherin, resulting Inhibitors,Modulators,Libraries in over accumulation of these adherens junction components and disruption of epi thelial integrity. During our analyses of awd function in the follicular epithelium, we also noted a proliferation Inhibitors,Modulators,Libraries ab normality in awd mutant cells that is reminiscent of the Notch signaling defect. This observation prompted us to re visit the original abnormal wing discs phenotype, which led to the discovery of the classic notched wing phenotype in flies carrying mosaic awd mutant clones. Notch pathway is a highly conserved cell cell communication pathway and functions to regulate many different cellular processes dur ing embryonic development and in adulthood. Canon ical Notch signaling requires binding of membrane bound Notch receptor to membrane bound ligand Delta Serrate Lag2 on the juxtaposed cells.

The interaction triggers proteolytic cleavage in the extracellular juxtamembrane re gion of Notch, separating the ligand bound extracellular domain and the membrane bound NEXT. NEXT is then subjected to intra membrane proteolysis by secretase. The Inhibitors,Modulators,Libraries proteolysis releases the intracellular domain of Notch, which translocates into the nucleus and regulates transcription of target genes by association with transcrip tional cofactors of the CBF1 Su Lag1 family. More recently, it has been shown that in some cell types, Notch entry into the endocytic pathway is critical for proper Notch activation and signaling.

Since Notch signaling may function either as a tumor suppressor or as an oncogene, depending on the tissue context, the functional relationship between Nm23 awd and Notch may provide important insights into the seemingly Inhibitors,Modulators,Libraries contra dictory roles of Nm23 in tumor progression. In addition, elucidating the more info Notch signaling defect in awd mutant cells should also shed light on the awd action in the endocytic pathway. In the present study, we show that awd function is re quired for proper Notch signaling in follicle cells and imaginal disc cells.