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Glycobiology Advance Access published online on September 13, 2006
Glycobiology, doi:10.1093/glycob/cwl049
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received March 30, 2006
Revised August 14, 2006
Accepted September 8, 2006

Article

Dependence of Neurotrophic Factor Activation of Trk Tyrosine Kinase Receptors on Cellular Sialidase

Alicja Woronowicz 1, Schammim R. Amith 1, Kristof De Vusser 2, Wouter Laroy 2, Roland Contreras 2, Sameh Basta 1, and Myron R. Szewczuk 1 *

1 Department of Microbiology & Immunology, Queen's University, Kingston, Ontario, K7L3N6, Canada
2 Fundamental and Applied Molecular Biology, Ghent University, Flanders Interuniversity Institute for Biotechnology (V.I.B.) Technologiepark 927 B-9052 Gent-Zwijnaarde Belgium

* To whom correspondence should be addressed.
Myron R. Szewczuk, E-mail: szewczuk{at}post.queensu.ca


  Abstract

A direct link between receptor glycosylation and activation following natural ligand interaction has not been observed. Here, we discover a membrane sialidase-controlling mechanism that depends on ligand binding to its receptor to induce enzyme activity which targets and desialylates the receptor and, consequently, causes the induction of receptor dimerization and activation. We also identify a specific sialyl {alpha}-2,3-linked {beta}-galactosyl sugar residue of TrkA tyrosine kinase receptor, which is rapidly targeted and hydrolyzed by the sialidase. Trk-expressing cells and primary cortical neurons following stimulation with specific neurotrophic growth factors express a vigorous membrane sialidase activity. Neuraminidase inhibitors, Tamiflu, BCX1812 and BCX1827, block sialidase activity induced by nerve growth factor (NGF) in TrkA-PC12 cells and by brain-derived neurotrophic factor (BDNF) in primary cortical neurons. In contrast, the neuraminidase inhibitor, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), specific for plasma membrane ganglioside Neu3 and Neu2 sialidases has no inhibitory effect on NGF-induced pTrkA. The GM1 ganglioside specific cholera toxin subunit B (CTX-B) applied to TrkA-PC12 cells has no inhibitory effect on NGF-induced sialidase activity. Neurite outgrowths induced by NGF-treated TrkA-PC12 and BDNF-treated TrkB-nnr5 cells are significantly inhibited by Tamiflu. Our results establish a novel mode of regulation of receptor activation by its natural ligand and define a new function for cellular sialidases.

Keywords: cell differentiation; cell signaling; receptor activation; sialic acid; TrkA tyrosine kinase receptor; trypanosome trans-sialidase; cellular sialidase.
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