UDP–sugar transporter implicated in glycosylation and processing of Notch

Abstract

Glycosylation modifies protein activities in various biological processes. Here, we report the functions of a novel UDP-sugar transporter (UST74C, an alternative name for Fringe connection (Frc)) localized to the Golgi apparatus in cellular signalling of Drosophila. Mutants in the frc gene exhibit phenotypes resembling wingless and Notch mutants. Both Fringe-dependent and Fringe-independent Notch pathways are affected, and both glycosylation and proteolytic maturation of Notch are defective in mutant larvae. The results suggest that changes in nucleotide-sugar levels can differently affect Wingless and two distinct aspects of Notch signalling.

Molecular Cloning and Characterization of a Human Multisubstrate Specific Nucleotide-sugar Transporter Homologous to Drosophila fringe connection

“…The interaction of the Notch receptor with its ligands, Serrate and Delta, is modulated by the addition of GlcNAc to an O-linked Fuc on the Notch by FRINGE enzyme (30 -33). In Drosophila, mutation of frc leads to a defect in Notch maturation (10). Here, HFRC1 exhibited an apparent K m value for UDP-GlcNAc comparable with that of FRC (8 versus 7.8 M, respectively).…”

“…Biochemical analysis of sqv-7 mutants has demonstrated defects in both chondroitin and heparan sulfate biosynthesis in vivo (8). Furthermore, Selva et al (9) and Goto et al (10) reported that the Drosophila melanogaster gene of fringe connection (frc) is involved in embryonic Wingless/Hedgehog and fibroblast growth factor signaling (9,10). Frc encodes a multisubstrate-specific NST that transfers UDP-sugars into the Golgi apparatus (9,10).…”

“…Furthermore, Selva et al (9) and Goto et al (10) reported that the Drosophila melanogaster gene of fringe connection (frc) is involved in embryonic Wingless/Hedgehog and fibroblast growth factor signaling (9,10). Frc encodes a multisubstrate-specific NST that transfers UDP-sugars into the Golgi apparatus (9,10). UDP-GlcUA and UDP-N-acetylglucosamine (UDP-GlcNAc) act as substrates for the synthesis of heparan sulfate.…”

GETDB, a database compiling expression patterns and molecular locations of a collection of gal4 enhancer traps

“…This set of strains has been used to identify a new gene involved in Notch signaling (Goto et al, 2001), and detailed analyses of the adult brain and embryonic PNS are under way (Tanaka et al, in prep; Uemura et al, in preparation). Most of the strains will be available from the Genetic Strain Research Center of NIG and from the Drosophila Genetic Resource Center, Kyoto Institute of Technology, and are expected to serve as valuable tools for the research community.…”

Neurogenetics and Pharmacology of Learning, Motivation, and Cognition

“…This gene encodes a sugar-transporter protein and has a role in the glycosylation of proteins that are expressed in the surface of cells (Selva et al, 2001), and in some cases, in development by regulating the surface presentation of gylycospylated proteins involved in cell fate decisions (Goto et al, 2001). Further clues into the function of Slc35d3 come from mice who carry inactivated copies of the gene and show striatal and motor abnormalities (Lu et al, 2008).…”