Journal of Biological Chemistry
Volume 286, Issue 6, 11 February 2011, Pages 4199-4208
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Glycobiology and Extracellular Matrices
Down-regulation of Chondroitin 4-O-Sulfotransferase-1 by Wnt Signaling Triggers Diffusion of Wnt-3a*

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During metazoan development, Wnt molecules are secreted from Wnt-producing cells, diffuse to target cells, and determine cell fates; therefore, Wnt secretion is tightly regulated. However, the molecular mechanisms controlling Wnt diffusion are not fully elucidated. The specific chondroitin sulfate (CS) structure synthesized by chondroitin-4-O-sulfotransferase-1 (C4ST-1) binds to Wnt-3a with high affinity (Nadanaka, S., Ishida, M., Ikegami, M., and Kitagawa, H. (2008) J. Biol. Chem. 283, 27333–27343). In this study we tested whether Wnt signaling regulates sulfation patterns of cell-associated CS chains by suppressing expression of C4ST-1 to trigger release of Wnt molecules from Wnt-producing cells. C4ST-1 expression was dramatically reduced in L cells that stably expressed Wnt-3a (L-Wnt-3a cells) and had CS with low affinity for Wnt-3a. Forced expression of C4ST-1 in L-Wnt-3a cells inhibited diffusion of Wnt-3a due to structural alterations in CS chains mediated by C4ST-1. Furthermore, sustained Wnt signaling negatively regulated C4ST-1 expression in a cell-autonomous and non-cell autonomous fashion. These results demonstrated that C4ST-1 is a key downstream target of Wnt signaling that regulates Wnt diffusion from Wnt-producing cells.

Chondroitin Sulfate
Extracellular Matrix
Glycosaminoglycan
Proteoglycan Structure
Signal Transduction
Sulfotransferase
Wnt Pathway

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*

This work was supported by the Scientific Research Promotion Fund from the Japan Private School Promotion Foundation and Grant-in-aid for Scientific Research-B 21390025 (to H. Kitagawa), and Grant-in-aid for Young Scientists (B) 20790081 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to S. N.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1–S5.