Defect in the gene that makes YAP might contribute to cancer

Johns Hopkins scientists have identified a protein in fruit flies whose counterpart product in humans may help cause cancer.

The researchers report in the Aug. 12 issue of Cell that a protein dubbed Yorkie directly controls the fruit fly's organ size and, when overabundant, causes increased cell growth and decreased cell death, hallmarks of cancer. Yorkie's relative in mammals, called YAP, appears to do the same thing, the researchers report, which suggests that in humans, a defect in the gene that makes YAP might contribute to cancer.

"Over the past few decades, science has identified a few so-called oncogenes, whose protein products act as accelerators and trigger abnormal cell growth," said Duojia Pan, Ph.D., who carried out most of the study at the University of Texas Southwestern Medical Center at Dallas before coming to the Johns Hopkins Institute for Basic Biomedical Sciences. "YAP seems to be another one and our lab is already investigating the amount of YAP protein in human tumors to see if excessive amounts are there."

The researchers also report Yorkie directly regulates the size of all the fruit fly's organs. "We were surprised to find that by adding Yorkie to levels above normal, the fruit fly's organs grew larger," said Pan. "Likewise, by removing Yorkie to levels below normal, the fruit fly's organs were smaller than usual."

The new findings build on Pan's earlier studies, which showed that fruit flies missing a gene called hippo developed tumors. That study revealed a tumor-suppression pathway involving proteins made by hippo and two other like-minded genes, all three of which function in a chain reaction to chemically add phosphate to other proteins, a process called phosphorylation.

"From those results, we predicted that another protein must be involved in the tumor-suppression pathway that is a target of the phosphorylation cascade," said Pan.

Yorkie turns out to be that "mystery protein," the researchers report. In their experiments, Pan and his colleagues show that the hippo phosphorylation cascade, by adding a phosphate group to the Yorkie protein, turns it off.

When the scientists engineered reduced levels of hippo and other proteins that keep Yorkie in check, Yorkie caused tissues to overgrow by prompting more cells to grow and fewer to die, the hallmarks of cancer.

Further experiments in the fruit fly that replaced Yorkie with YAP showed both proteins play similar roles, suggesting YAP might participate in a tumor-related pathway in mammals.

Pan is now trying to identify the signal that tells genes like hippo to turn on or off once an organ grows to the appropriate size. That signal could be harnessed for therapeutics against cancer.

The authors of the paper besides Pan are Shian Wu from Hopkins, and Jianbin Huang, Jose Barrera and Krista Matthews from UT Southwestern. The study was funded by the National Institutes of Health.