STUDIES OF PROTEINS THAT TRANDUCE HEDGEHOG SIGNALING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Signaling by Hh proteins shapes the development of many tissues and organs in both vertebrates and invertebrates. In human, sheep, fish, and mouse embryos, reduced Hh signaling causes sever holoprosencephaly and cyclopia (the formation of only one eye). In human adults, Hh signaling is critical for certain stem cell populations, and increased Hh signaling can lead to cancers of the skin, cerebellum, muscle, digestive tract, pancreas, and prostate. Several small molecule Hh agonists and antagonists are currently in development and hold great promise as effective drugs, but the biology of Hh protein function and signaling is complex and many significant questions remain. Understanding the mechanism and regulation of Hh signaling is an important problem with immediate medical implications. hh was first identified as a gene that is required for segmentation of the Drosophila embryo, and subsequent to its molecular isolation by my group and others, orthologs in vertebrates were also isolated and characterized. Synthesis and processing of Hh is both complex and essential for its function. In Hh-receiving cells, two membrane-bound proteins, Ptc and Smoothened (Smo) mediate the Hh response. The Ptc sequence suggests that it is a 12-transmembrane protein with structural homology to the bacterial efflux transporter AcrB. AcrB forms a homotrimer that pumps out substrates that include bile acids and their derivatives; at this time, we do not know if Ptc shares any functional homology with AcrB, and neither its structure nor its putative substrate specificity is known. Our current interest in accessing the computational resources of the CGL is driven by our desire to analyze the conservation of the large family of Patched proteins that have been identified. Our goal is to define the complete family, identify conserved domains and identify conserved residues within the conserved domains in order to both rationalize the nomenclature for Patched proteins and to guide functional studies.