The goal of my research is to elucidate the poorly understood mechanisms involved in Hedgehog (Hh) and Wnt signal transduction, two related pathways that play critical roles in development, regeneration and cancer.

The Hh and Wnt ligands are both lipid-modified secreted proteins that share similarities in signaling mechanisms at the cell surface. These stimuli are propagated across the plasma membrane through two homologous receptors of the class F GPCR superfamily, Smoothened (SMO) and Frizzled (FZ), respectively. Although structurally similar to classical GPCRs, the mechanisms by which these 7-transmembrane receptors signal across membranes and how their activation triggers downstream even...

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The goal of my research is to elucidate the poorly understood mechanisms involved in Hedgehog (Hh) and Wnt signal transduction, two related pathways that play critical roles in development, regeneration and cancer.

The Hh and Wnt ligands are both lipid-modified secreted proteins that share similarities in signaling mechanisms at the cell surface. These stimuli are propagated across the plasma membrane through two homologous receptors of the class F GPCR superfamily, Smoothened (SMO) and Frizzled (FZ), respectively. Although structurally similar to classical GPCRs, the mechanisms by which these 7-transmembrane receptors signal across membranes and how their activation triggers downstream events remain largely obscure.

Recently, I identified cholesterol as the endogenous ligand that activates SMO in relaying Hh signals to the cytoplasm and defined the structural and oncogenic basis of SMO activation. I have also reconstituted SMO in membrane nanodiscs, validated by determining its Cryo-EM structure.

In the first project, I will utilize this unique biochemically-tractable membrane system, combining with chemical and cell biology, to elucidate the mechanism of Hh signal transduction through SMO, its regulation by sterols, and therapeutic implications.

In the second project, I will employ similar approaches that I have established, to study Wnt production, transportation and signal transduction through Frizzled.

At Baylor College of Medicine, I have coordinated potential collaborations with proteomic, microscopy and drug discovery centers, as well as those providing complementary expertise in cancer biology and disease models. The immediate goal is to gain a complete mechanistic understanding of signal transduction in the Hh and Wnt pathways. Intermediate-term goals include identification of novel targets and strategies for blocking oncogenic Hh and Wnt signaling.

The ultimate goal is to develop new and better therapies for cancers driven by these two pathways.

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