Proteoglycans, as components of extracellular matrices, participate in tissue morphogenesis and cell differentiation. On cell surfaces, they bind extracellular proteins, organize other cell surface molecules, and engage in endocytosis and cell adhesion. In-bred animals bearing mutations in proteoglycan assembly suffer from disproportionate dwarfisms. Numerous disorders in humans, including tumor formation correlate with aberrations in proteoglycan composition. The long range objective of this proposal is to analyze the relationship of proteoglycan structure, assembly and activity. These relationships will be studied in Chinese hamster ovary cells through mutations that block proteoglycan synthesis. Methods are described to study the glycosyltransferases responsible for assembly of the linkage tetrasaccharide common to chondroitin and heparan sulfate. These studies will establish if the individual biosynthetic pathways diverge during the assembly of the linkage region. Characterization of other mutants defective in the formation of chondroitin sulfate or heparan sulfate should reveal how the biosynthetic pathways are coordinated. Selection of mutations that augment the content of proteoglycans will identify rate-limiting enzymes and regulatory factors present in the system. Mutational studies permit the analysis of proteoglycan function without removing them from their normal cellular context. Studies of mutants lacking all proteoglycans demonstrated that these molecules are essential for endocytosis of thrombospondin and for cell attachment to defined extracellular matrices. These findings justify additional studies of mutants since other functions for proteoglycans may emerge. Dissection of the biosynthetic system by mutation should help define appropriate enzymatic targets for the development of metabolic inhibitors. This might lead to pharmacologic strategies for controlling the composition of proteoglycans in healthy and diseased tissues.

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National Institute of General Medical Sciences (NIGMS)
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Pathobiochemistry Study Section (PBC)
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University of Alabama Birmingham
Schools of Dentistry
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Thieker, David F; Xu, Yongmei; Chapla, Digantkumar et al. (2018) Downstream Products are Potent Inhibitors of the Heparan Sulfate 2-O-Sulfotransferase. Sci Rep 8:11832
Gordts, Philip L S M; Esko, Jeffrey D (2018) The heparan sulfate proteoglycan grip on hyperlipidemia and atherosclerosis. Matrix Biol 71-72:262-282
van Wijk, Xander M; Döhrmann, Simon; Hallström, Björn M et al. (2017) Whole-Genome Sequencing of Invasion-Resistant Cells Identifies Laminin ?2 as a Host Factor for Bacterial Invasion. MBio 8:
Bergfeld, Anne K; Lawrence, Roger; Diaz, Sandra L et al. (2017) N-glycolyl groups of nonhuman chondroitin sulfates survive in ancient fossils. Proc Natl Acad Sci U S A 114:E8155-E8164
Dwyer, Chrissa A; Esko, Jeffrey D (2016) Glycan susceptibility factors in autism spectrum disorders. Mol Aspects Med 51:104-14
Gordts, Philip L S M; Nock, Ryan; Son, Ni-Huiping et al. (2016) ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest 126:2855-66
Zaiss, Anne K; Foley, Erin M; Lawrence, Roger et al. (2016) Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo. J Virol 90:412-20
Berbée, Jimmy F P; Boon, Mariëtte R; Khedoe, P Padmini S J et al. (2015) Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat Commun 6:6356
Mooij, Hans L; Bernelot Moens, Sophie J; Gordts, Philip L S M et al. (2015) Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans. J Lipid Res 56:665-73
Wen, Jianzhong; Xiao, Junyu; Rahdar, Meghdad et al. (2014) Xylose phosphorylation functions as a molecular switch to regulate proteoglycan biosynthesis. Proc Natl Acad Sci U S A 111:15723-8

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