The protagonist of the discovery is the GLI1 protein, which is critical for cell development but has also been implicated in some cancers. The Hedgehog Signaling Pathway, also known as HH, normally activates GLI1. However, scientists have known for nearly a decade that crosstalk, or interaction, between the HH and mitogen-activated protein kinase pathways has a role in cancer development.
“In some cases, proteins from one pathway can turn on proteins from another pathway,” said lead author A. Jane Bardwell, a project scientist in UCI’s Department of Developmental and Cell Biology. “It’s a complex system. We wanted to understand Molecular mechanisms leading to GLI1 activation by proteins in the MAPK pathway”.
GLI1 normally forms a strong binding to a protein called SUFU. This protein inhibits GLI1, preventing it from penetrating the nucleus and turning on the gene. The researchers examined seven sites on the GLI1 protein that may be phosphorylated or have a phosphate group transferred to it.
“We identified three sites that can be phosphorylated that are involved in weakening the binding between GLI1 and SUFU,” said Lee Bardwell, professor of developmental and cell biology, whose lab led the project. “This process activates GLI1, enabling it to enter the nucleus, where it can cause uncontrolled growth, leading to cancer.”
He noted that phosphorylation at all three sites caused GLI1 to escape SUFU at a significantly higher level than if only one or even two of the sites received the phosphorylated group.
The discovery is an important step toward more effective and personalized cancer treatment. “If we can get an accurate picture of what’s going on with a cancer or a specific tumor, it may be possible to develop a drug that targets a specific tumor or individual patient,” Bardwell said. This will allow us to treat these diseases without the toxicity of basic chemotherapy. In addition, many tumors from the same cancer have different mutations between individuals. Ultimately, it may be feasible to screen tumors to develop the best method for each individual. “