The long term objective of this research is to understand the molecular mechanisms that control cell-cell signaling in developing and adult tissues. Hedgehog (Hh) signaling proteins control cell fates and proliferation during animal development by regulating the specific gene expression. In vertebrates, Hh proteins pattern diverse tissues such as the developing limb, spinal column, and brain. The membrane protein Patched (Ptc) opposes Hh to inactivate specific gene expression. In Drosophila, ptc mutations cause misexpression of Hh target genes and result in abnormal development and cell proliferation. Mutations in a human homolog of ptc, PTCH1 lead to the very common skin tumor, basal cell carcinoma, and to the brain tumor, medulloblastoma. PTCH1 is also mutated in the basal cell nevus syndrome, an inherited disorder characterized by many developmental defects and tumors. The molecular mechanisms of Hh signal reception and transduction are largely unknown. Central to understanding the role of Hh signaling in development and disease is learning how Ptc functions and identifying proteins with which it interacts. Ptc is proposed to bind Hh proteins and to associate with and regulate, Smoothened, (Smo), a membrane protein required for Hh signaling. Ptc also sequesters Hh to limit its range of action. How and where Ptc mediates these important regulatory processes is not known. Ptc may function in vesicle movement as suggested by its sequence similarity to NPC1, a membrane protein implicated in the intracellular trafficking of cholesterol. The proposed studies will identify the critical functional domains of Ptc and characterize the cellular localization of Ptc and its interacting proteins following ligand binding. Using Drosophila, new components of Hh signaling will be identified by a genetic screen involving a specific ptc phenotype.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037505-05
Application #
6636985
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Klein, Steven
Project Start
1999-04-01
Project End
2004-07-31
Budget Start
2003-02-01
Budget End
2004-07-31
Support Year
5
Fiscal Year
2003
Total Cost
$210,686
Indirect Cost
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Bailey, Evans C; Zhou, Lei; Johnson, Ronald L (2003) Several human PATCHED1 mutations block protein maturation. Cancer Res 63:1636-8
Bailey, Evans C; Milenkovic, Ljiljana; Scott, Matthew P et al. (2002) Several PATCHED1 missense mutations display activity in patched1-deficient fibroblasts. J Biol Chem 277:33632-40
Johnson, Ronald L; Zhou, Lei; Bailey, Evans C (2002) Distinct consequences of sterol sensor mutations in Drosophila and mouse patched homologs. Dev Biol 242:224-35
Johnson, R L; Milenkovic, L; Scott, M P (2000) In vivo functions of the patched protein: requirement of the C terminus for target gene inactivation but not Hedgehog sequestration. Mol Cell 6:467-78