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Glycobiology Advance Access published online on July 7, 2004
Glycobiology, doi:10.1093/glycob/cwh123
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Received May 4, 2004
Revised June 28, 2004
Accepted June 29, 2004

ORIGINAL ARTICLES

Trypanosome trans-sialidase targets TrkA tyrosine kinase receptor and induces receptor internalization and activation

Alicja Woronowicz 1, Kristof De Vusser 2, Wouter Laroy 2, Roland Contreras 2, Susan O. Meakin 3, Gregory M. Ross 4, 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
3 Laboratory of Neural Signaling, Cell Biology Group, Robarts Research Institute, London, Ontario, N6A 5K8, Canada
4 Department of Physiology, Queen's University, Kingston, Ontario, K7L3N6, Canada

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


  Abstract

Trypanosome trans-sialidase (TS) is a sialic acid-transferring enzyme which hydrolyzes {alpha}2,3-linked sialic acids and transfers them to acceptor molecules. Here, we show that a highly purified recombinant TS derived from T. cruzi parasites targets TrkA receptors on TrkA-expressing PC12 cells and colocalizes with TrkA internalization and phosphorylation (pTrkA). Maackia amurensis lectin II (MAL-II) and Sambucus nigra lectin (SNA) block TS binding to TrkA-PC12 cells in a dose-dependent manner with subsequent inhibition of TS colocalization with pTrkA. Cells treated with lectins alone do not express pTrkA. The catalytically inactive mutant TS{Delta}Asp98-Glu also binds to TrkA-expressing cells, but is unable to induce pTrkA. TrkA-PC12 cells treated with a purified recombinant {alpha}2,3-neuraminidase (Streptococcus pneumoniae) express pTrkA. Wild type TS but not the mutant TS{Delta}Asp98-Glu promotes neurite outgrowth in TrkA-expressing PC12 cells. In contrast, these effects are not observed in TrkA deficient PC12nnr5 cells, but are reestablished in PC12nnr5 cells stably transfected with TrkA and are significantly blocked by inhibitors of tyrosine kinase (K-252a) and MAP/MEK protein kinase (PD98059). Together these observations suggest for the first time that hydrolysis of sialyl {alpha}-2,3-linked {beta}-galactosyl residues of TrkA receptors plays an important role in TrkA receptor activation, sufficient to promote cell differentiation (neurite outgrowth) independent of nerve growth factor.

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