Biochemical Mechanisms of Hedgehog Signaling.
First discovered and studied in Drosophila, the Hedgehog (Hh) signaling pathway regulates cell proliferation, differentiation, and patterning in a range of tissues during animal development. Mutations that cause aberrant Hh signaling lead to birth defects in humans, and genes encoding
Hh pathway proteins can
function as human oncogenes or tumor suppressor genes. Prominent examples of Hh-induced carcinogenesis include medulloblastoma, the most common pediatric brain tumor, and basal cell carcinoma, the most common type of skin cancer, both of which often carry mutations that lead to unchecked Hh signaling. In adults, Hh signaling is thought to regulate the function of tissue stem cells and, under pathological conditions, to sustain tumor stem cells. All things considered, therapeutics and diagnostics based on this pathway hold great promise in cancer and regenerative medicine.
Despite its importance, the biochemical mechanisms that drive Hedgehog signaling remain poorly understood in vertebrates. We study three mysterious steps in Hedgehog signaling:
1. The regulation of Smoothened, an oncoprotein and cancer drug target,
by the Hedgehog receptor Patched.
2. The mechanism by which Smoothened relays the Hedgehog signals
to downstream effectors.
3. The biochemical mechanism by which the Gli transcription factors
are regulated in response to signaling.
Major advances in mammalian Hedgehog signaling have come from the discovery that Hedgehog signaling is orchestrated at the primary cilium. Most proteins in the Hh pathway, including Patched, Smoothened and the Glis, localize in cilia and it is likely that many of the critical reactions in the pathway occur within this specialized compartment. We strive to understand how the carefully choreographed trafficking of Hedgehog pathway proteins at primary cilia drives signal transduction
in this organelle.