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J. Biol. Chem., Vol. 281, Issue 23, 15821-15828, June 9, 2006

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Hyaluronan Synthesis Induces Microvillus-like Cell Surface Protrusions^*

Anne Kultti¹, Kirsi Rilla¹, Riikka Tiihonen, Andrew P. Spicer, Raija H. Tammi, and Markku I. Tammi²

From the Department of Anatomy, University of Kuopio, FIN-70211 Kuopio, Finland and Texas A&M University System Health Science Center, Institute of Biosciences and Technology, Houston, Texas 77030

Hyaluronan synthases (HASs) are plasma membrane enzymes that simultaneously elongate, bind, and extrude the growing hyaluronan chain directly into extracellular space. In cells transfected with green fluorescent protein (GFP)-tagged Has3, the dorsal surface was decorated by up to 150 slender, 3–20-µm-long microvillus-type plasma membrane protrusions, which also contained filamentous actin, the hyaluronan receptor CD44, and lipid raft microdomains. Enzymatic activity of HAS was required for the growth of the microvilli, which were not present in cells transfected with other GFP proteins or inactive GFP-Has3 mutants or in cells incubated with exogenous soluble hyaluronan. The microvilli induced by HAS3 were gradually withered by introduction of an inhibitor of hyaluronan synthesis and rapidly retracted by hyaluronidase digestion, whereas they were not affected by competition with hyaluronan oligosaccharides and disruption of the CD44 gene, suggesting independence of hyaluronan receptors. The data bring out the novel concept that the glycocalyx created by dense arrays of hyaluronan chains, tethered to HAS during biosynthesis, can induce and maintain prominent microvilli.

Received for publication, December 1, 2005 , and in revised form, March 21, 2006.

^* This work was supported by the Academy of Finland, Grants 40807 and 54062 (to M. I. T.) and by grants from the Sigrid Juselius Foundation (to M. I. T.), Emil Aaltonen Foundation (to A. K. and K. R.), Finnish Cultural Foundation (to A. K.), Kuopio University Foundation (to A. K. and K. R.), Finnish Cancer Foundation (to R. H. T.), The North Savo Cancer Foundation (to A. K. and K. R.), The Finnish Technology Centre TEKES (to M. I. T.), and the EVO funds of Kuopio University Hospital (to M. I. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two supplemental movies showing MCF-7 cells expressing GFP-HAS3.

¹ Both authors contributed equally to this work

² To whom correspondence should be addressed: Dept. of Anatomy, University of Kuopio, P. O. B. 1627, FIN-70211 Kuopio, Finland. Tel.: 358-17-163019; 358-40-7674826; Fax +358-17-163032; E-mail: tammi{at}uku.fi.

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