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August 22, 2002
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Hedgehog Signaling Pathway Has New Route  

The celebrated signaling pathway called Hedgehog, crucial in proper embryo development and implicated in some cancers, has a new twist, Johns Hopkins scientists report in the August 22 issue of Nature.

The Hedgehog signal, named for the gene and the protein that trigger it, guides developing embryos to form patterns of cells by telling neighboring cells what they should become and when they should begin growing. When turned on later in life, the Hedgehog signal can lead to cancer. The Hopkins research proves that the two proteins that stop or relay Hedgehog's message interact differently than others have claimed.

By creating new ways to highlight and count these two proteins, named Patched and Smoothened, and see exactly where they are in cells, research associate Jussi Taipale, Ph.D., and his colleagues prove that the two interact only indirectly. They don't bind each other; they aren't even near each other, say the researchers.

"We now know Patched controls Smoothened indirectly, but the question of exactly how is very much open for debate," says Philip Beachy, Ph.D., professor of molecular biology and genetics in Hopkins' Institute for Basic Biomedical Sciences. "The answer to controlling the Hedgehog signal does not lie in preventing Patched and Smoothened from binding each other, because they just don't do it."

The Hedgehog gene came by its name after studies of fruit flies lacking it revealed that cell types were jumbled in these knockouts, instead of organized in the neat lines of normal flies. The jumbled cells, the scientists decided, resembled the round, porcupine-like critter.

Scientists already knew that Patched turned off Hedgehog's signal and Smoothened passed it along. Other researchers in the mid 90s claimed that Patched directly bound to Smoothened to block it when Hedgehog itself wasn't around. With their new discoveries, however, the Hopkins team determined that it takes just one Patched to cut the activity of 50 Smoothened molecules in half.

"We saw that a little Patched goes a long way," says Beachy, also a Howard Hughes Medical Institute investigator. "If it blocked the signal by binding directly to Smoothened, as was claimed in the past, it would take a lot more. Instead, Patched acts catalytically -- it affects Smoothened without being altered itself."

Patched's similarity to some proteins found in bacteria may help explain how it does work, the scientists suggest. With identical amino acids in key regions and a very similar overall shape, Patched may have the same function as these bacterial proteins, which move various things -- from charged atoms to small molecules -- across cell membranes.

Pursuing this idea, the Hopkins team searched published medical papers for accounts of patients with Gorlin's syndrome, who have a dramatically increased risk of cancer because they have only one working copy of Patched. While the vast majority of cases were due to deletion or shortening of one copy of the Patched gene, Taipale discovered six patients in whom the loss of a working Patched protein was due to mutations in the gene that altered a single building block in the protein.

"These mutations are in the same region where identical, crucial amino acids sit in similar bacterial proteins that function as transporters," says Beachy. "In the bacterial proteins, if these amino acids are changed, the transport function is blocked. If that's happening to Patched in these cases of Gorlin's syndrome, whatever Patched might transport could be what's blocking Smoothened."

Unraveling the details of the Hedgehog pathway may have important clinical implications because of Hedgehog's critical role in embryo development and some cancers, notes Beachy. Hedgehog has been identified in skin cancer, medulloblastoma (a childhood brain cancer), and rhabdomyosarcoma (a childhood muscle cancer).

"Gorlin's syndrome patients have a dramatically increased risk for cancer, because if their one working copy of Patched gets damaged, the brake on Hedgehog is lost," says Beachy. "They are particularly at risk for skin cancers, because ultraviolet light is very good at zapping DNA. Figuring out a way to increase Patched's effects or shut off Smoothened could go a long way to helping these people."

The studies were funded by the National Institutes of Health and the Howard Hughes Medical Institute. Authors on the report are Taipale, Beachy, Michael Cooper and Tapan Maiti, all of The Johns Hopkins University School of Medicine.

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