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School of Medicine
DJ Pan of Molecular Biology and Genetics
on hippo and cancer
The Hippo pathway has been well characterized in flies; what was the difficulty in uncovering its role in mammals?
PAN: I’ve always believed that the Hippo pathway has the same function in flies and mammals. However, it’s been difficult to prove this idea because although we knew of the mammalian counterparts to fly Hippo pathway proteins, nobody, including us, could link these counterparts into a single pathway. In our recent paper, we’ve now identified the phosphorylation site in mammals that indicates pathway activity, so now we can use a phosphorylation-specific antibody as a read out to identify this pathway in mammals.
Was it surprising to find that a single phosphorylation event accounts for the giant organ phenotype?
PAN: Yes, we were pleasantly surprised to discover that the powerful growth-regulatory activity of the Hippo pathway can be reduced to a single phosphorylation event on a single site in Yki or its mammalian counterpart Yap. Realizing how nature solved a complex problem with such a simple strategy is one of those “eureka moments” for us.
How important is this pathway?
PAN: This work is still in its early days, but I really think the discovery of the Hippo pathway will rival the discovery of other important signaling pathways such as Notch, Hedgehog and Wnt. There aren’t many canonical signaling pathways in development; a very limited number of pathways control everything. So to uncover a new pathway is an important discovery and opens up a whole range of questions to answer.
What areas of research do you think will stem from your recent findings on the Hippo pathway?
PAN: There are two main areas for future Hippo work. One is the connection between this pathway and cancer. Activation of the Hippo pathway prohibits cell proliferation and promotes cell death. So if we identify human cancers caused by aberrant Hippo signaling, we might identify new targets for cancer therapeutics. I also think that studying this pathway could reveal the mystery of how an organ is instructed to grow to a characteristic size. One may utimately be able to harness the power of this pathway to engineer organs of predetermined size.