Lysosomes are the primary site for degradation of normal cellular constituents. Over 30 inheritable """"""""storage diseases"""""""" are caused by specific defects in lysosomal hydrolase activities. Defective lysosomal function is also characteristic of aging and various nutritional disorders. Lysosomal injury during acquired diseases results in extracellular release of activated hydrolase which often produces necrosis and cell death. The mannose 6-phosphate receptor is responsible for localization of many hydrolases in lysosomes. It binds the hydrolases immediately after their synthesis and facilitates their packaging into lysosomes. The receptor also functions on the cell surface to facilitate removal of acid hydrolases from extracellular sites. The long range goal is to determine the molecular basis of mannose 6-phosphate receptor function. Recombinant DNA techniques will be used to introduce structural changes in the receptor, biologic methods will be used to examine their effects on specific aspects of receptor function. The immediate objectives of this proposal, namely to clone a cDNA encoding the mannose 6-phosphate receptor and determine the structure of the receptor, provide the basis for achieving this goal. These studies will contribute to our understanding of lysosome biogenesis, intracellular membrane trafficking and protein sorting.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Pathobiochemistry Study Section (PBC)
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Tufts University
Schools of Medicine
United States
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Cuozzo, J W; Tao, K; Wu, Q L et al. (1995) Lysine-based structure in the proregion of procathepsin L is the recognition site for mannose phosphorylation. J Biol Chem 270:15611-9
Cuozzo, J W; Sahagian, G G (1994) Lysine is a common determinant for mannose phosphorylation of lysosomal proteins. J Biol Chem 269:14490-6
Tao, K; Stearns, N A; Dong, J et al. (1994) The proregion of cathepsin L is required for proper folding, stability, and ER exit. Arch Biochem Biophys 311:19-27
Dong, J M; Sahagian, G G (1990) Basis for low affinity binding of a lysosomal cysteine protease to the cation-independent mannose 6-phosphate receptor. J Biol Chem 265:4210-7
Stearns, N A; Dong, J M; Pan, J X et al. (1990) Comparison of cathepsin L synthesized by normal and transformed cells at the gene, message, protein, and oligosaccharide levels. Arch Biochem Biophys 283:447-57
Prence, E M; Dong, J M; Sahagian, G G (1990) Modulation of the transport of a lysosomal enzyme by PDGF. J Cell Biol 110:319-26
Kiess, W; Thomas, C L; Greenstein, L A et al. (1989) Insulin-like growth factor-II (IGF-II) inhibits both the cellular uptake of beta-galactosidase and the binding of beta-galactosidase to purified IGF-II/mannose 6-phosphate receptor. J Biol Chem 264:4710-4
Dong, J M; Prence, E M; Sahagian, G G (1989) Mechanism for selective secretion of a lysosomal protease by transformed mouse fibroblasts. J Biol Chem 264:7377-83
Jin, M; Sahagian Jr, G G; Snider, M D (1989) Transport of surface mannose 6-phosphate receptor to the Golgi complex in cultured human cells. J Biol Chem 264:7675-80
Kiess, W; Blickenstaff, G D; Sklar, M M et al. (1988) Biochemical evidence that the type II insulin-like growth factor receptor is identical to the cation-independent mannose 6-phosphate receptor. J Biol Chem 263:9339-44