Hedgehog signaling in development and cancer
The Hedgehog (Hh) family of secreted signaling proteins plays fundamental roles in the patterning of central nervous system (CNS), limb, teeth, lung, and many other structures. Loss of or decrease in the Hh signaling pathway activity results in severe developmental birth defects such as holopresencephaly (HPE), a striking malformation of head and brain that includes cyclopia and loss of midline forebrain and facial structures. In addition to developmental abnormalities, inappropriate activation of the Hh signaling pathway is also associated with several common types of human cancer including basal cell carcinoma, medulloblastoma, and many others.
The research in Dr. Wang’s lab currently focuses on three areas. The first area is to elucidate the molecular mechanism of Hh signal transduction. In the absence of Hh signal, the Hh receptor Patched (Ptc) suppresses the activity of Smoothened (Smo), an atypical G-protein coupled receptor. Gli2 and Gli3 transcription factors, the Hh signaling transcriptional mediators, are proteolytically processed into the repressors. Thus, the Hh pathway is turned off. The binding of Hh ligand to Ptc alleviates the Ptc suppression on Smo. The Smo subsequently transduces signals to the cytoplasmic Hh pathway components and ultimately inhibits Gli2 and Gli3 processing and converts them into activators. There are many enzymes and effectors involved in Gli2 and Gli3 processing and activation. Subcellular localization is also likely to play a role. Our objective is to elucidate the molecular mechanism of Gli2 and Gli3 processing and activation by Hh signaling using biochemical, cell biological, and genetic approaches.
The second area is to understand how Hh signaling controls neural tube and limb patterning. The role of Hh signaling in neural tube and limb patterning has been well established. It is generally believed that the Hh signal gradient specifies different neuronal cell types in the developing neural tube and patterns limb digits with right number and polarity. However, how the Hh signal gradient is interpreted and translated into patterning information remains elusive. Our goal is to address this important question using the mouse and chick models.
The third area is to understand how Hh signaling is abnormally activated in cancer. The aberrant activation of the Hh pathway is associated with several types of human cancer including basal cell carcinoma, medulloblastoma, breast and ovarian cancers, etc. The abnormal Hh signaling may be caused by an increased Hh expression or mutations in the Hh pathway components. This will ultimately activate Gli2 and Gli3, which in turn upregulates Gli1 RNA expression. Our goal is to understand how Gli proteins get activated in Hh signaling associated cancer cells. As research progresses quickly, anyone who is interested in the research of Dr. Wang’s lab should contact him for the most up-to-date research projects.
Dr. Wang's Email: email@example.com