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Published 27 September 2004. doi:10.1083/jcb.200403077
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 7, 1069-1079
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Article

 Regulation of Notch signaling by Drosophila heparan sulfate 3-O sulfotransferase

Keisuke Kamimura1,2, John M. Rhodes3, Ryu Ueda4, Melissa McNeely5, Deepak Shukla5, Koji Kimata2, Patricia G. Spear5, Nicholas W. Shworak3, and Hiroshi Nakato1

1 Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455
2 Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan
3 Section of Cardiology and Angiogenesis Research Center, Department of Medicine, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756
4 Invertebrate Genetics Laboratory, Genetic Strain Research Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan
5 Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

Address correspondence to Hiroshi Nakato, Dept. of Genetics, Cell Biology, and Development, University of Minnesota, 6-160 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455. Tel.: (612) 625-1727. Fax: (612) 626-5652. email: nakat003{at}umn.edu

Heparan sulfate (HS) regulates the activity of various ligands and is involved in molecular recognition events on the cell surface and in the extracellular matrix. Specific binding of HS to different ligand proteins depends on the sulfation pattern of HS. For example, the interaction between antithrombin and a particular 3-O sulfated HS motif is thought to modulate blood coagulation. However, a recent study of mice defective for this modification suggested that 3-O sulfation plays other biological roles. Here, we show that Drosophila melanogaster HS 3-O sulfotransferase-b (Hs3st-B), which catalyzes HS 3-O sulfation, is a novel component of the Notch pathway. Reduction of Hs3st-B function by transgenic RNA interference compromised Notch signaling, producing neurogenic phenotypes. We also show that levels of Notch protein on the cell surface were markedly decreased by loss of Hs3st-B. These findings suggest that Hs3st-B is involved in Notch signaling by affecting stability or intracellular trafficking of Notch protein.

Key Words: 3-O sulfation; heparan sulfate proteoglycan; Notch signaling; transgenic RNAi; Drosophila

D. Shukla's present address is Dept. of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612.

Abbreviations used in this paper: ACV, anterior cross vein; A/P, anterior–posterior; AT, antithrombin; BDGP, Berkeley Drosophila Genome Project; ct, cut; Dl, Delta; dpp, decapentaplegic; dx, deltex; D/V, dorsal–ventral; E(spl)C, Enhancer of split Complex; gD, glycoprotein D; HS, heparan sulfate; HS3ST, HS 3-O sulfotransferase; HSPG, HS proteoglycan; HSV, herpes simplex virus; IR, inverted repeat; kuz, kuzbanian; N, Notch; NECD, extracellular domain of N protein; neur, neuralized; NICD, intracellular domain of N protein; RNAi, RNA interference; sca, scabrous; Ser, Serrate; SMC, sensory organ mother cell; ST, sulfotransferase; Su(H), Suppressor of Hairless; UAS, upstream activating sequence; vg, vestigial; wg, wingless.


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