In a result with implications for future anti-cancer research, researchers have discovered that a fundamental, but error-prone, developmental pathway based on the protein Hedgehog has a hitherto unrecognised first step1.
The researchers report that the pathway kicks off when several unattached Hedgehog proteins are drawn together by electrostatic interactions between amino acids at the proteins' periphery. The nanoscale cluster that forms is the first seed of a multi-stage aggregation process that finally yields a mature Hedgehog mega-cluster. Only then is Hedgehog ready to begin the long journey away from its parent cell and to do its best — or worst.
"Identifying this initial step might help other scientists design an anti-cancer drug that could stall a mutant Hedgehog pathway in the most effective way possible because they could target it at the very source itself," lead researcher Neha Vyas says.
The researchers took a cue from earlier work that had predicted which of Hedgehog's amino acids were most likely to set up the electrostatic interaction. When the team used a directed mutation to deactivate one of the main suspects — a single lysine molecule — the normal mega-clusters did not form and the long-range developmental effects so typical of Hedgehog were shut down.
Ways to rein in the Hedgehog pathway have been sought ever since it was realized that natural mutation-based errors can actually over-activate the Hedgehog circuit, resulting in cancers such as small cell lung, pancreatic and prostrate cancers that are very malignant and difficult to treat. But as yet no Hedgehog antagonist has been cleared for human use, and the most promising candidate, cyclopamine, does not target Hedgehog itself, but a secondary protein of the pathway.
The team hopes to work towards a drug which can safely defuse the hyper Hedgehogs that cause such biological mayhem.
