INSIGHT INTO HIPPOSIGNLING PATHWAY AND CLINICAL IMPLICATIONS

The pace of discovery in the Hpo signaling field over the past few years has been remarkable, and because of its many advantages for gene discovery and characterization, research in Drosophila has continued to play a leading role. Substantial progress in identifying pathway components has been made recently, but we still lack a mechanistic understanding of crucial steps in the pathway, such as how the activity of the Hpo kinase is controlled by upstream regulators, or how the levels of Wts protein are controlled by Dachsand Zyx. Attaining these mechanistic insights will require substantial investments in both biochemical approaches (eg to reconstitute key steps in signal transduction in vitro), and better reagents for imaging steps in signal transduction. Reagents that would enable discrete identification and localization of active versus inactive isoforms of pathway components would be especially valuable. In short, in a field that has been dominated by geneticists, opportunities for talented biochemists and cell biologists abound. One of the remarkable features of the pathway is the number of different inputs into upstream regulation. A key challenge for the future is to understand how all of the different inputs into the pathway are related to each other. A further challenge will be to understand how diverse inputs are integrated to achieve appropriate levels of Yki activity. Another continuing challenge is to understand how the Hpo pathway is integrated with other growth control pathways. To date most research has focused on a limited set of partners and downstream target genes, and the full extent and cell type diversity of transcriptional responses to Yki activity remains an open question.