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Published online 16 October 2006. doi:10.1083/jcb.200605090
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 2, 293-303
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Article

 Protein tyrosine phosphatase TbPTP1: a molecular switch controlling life cycle differentiation in trypanosomes

Balázs Szöor1,2, Jude Wilson2, Helen McElhinney1,2, Lydia Tabernero2, and Keith R. Matthews1,2

1 Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3JT, Scotland, UK
2 Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, UK

Correspondence to Lydia Tabernero: lydia.tabernero{at}man.ac.uk; or Keith R. Matthews: keith.matthews{at}ed.ac.uk

Differentiation in African trypanosomes (Trypanosoma brucei) entails passage between a mammalian host, where parasites exist as a proliferative slender form or a G0-arrested stumpy form, and the tsetse fly. Stumpy forms arise at the peak of each parasitaemia and are committed to differentiation to procyclic forms that inhabit the tsetse midgut. We have identified a protein tyrosine phosphatase (TbPTP1) that inhibits trypanosome differentiation. Consistent with a tyrosine phosphatase, recombinant TbPTP1 exhibits the anticipated substrate and inhibitor profile, and its activity is impaired by reversible oxidation. TbPTP1 inactivation in monomorphic bloodstream trypanosomes by RNA interference or pharmacological inhibition triggers spontaneous differentiation to procyclic forms in a subset of committed cells. Consistent with this observation, homogeneous populations of stumpy forms synchronously differentiate to procyclic forms when tyrosine phosphatase activity is inhibited. Our data invoke a new model for trypanosome development in which differentiation to procyclic forms is prevented in the bloodstream by tyrosine dephosphorylation. It may be possible to use PTP1B inhibitors to block trypanosomatid transmission.

Abbreviations used in this paper: BZ3, 3-(3,5-Dibromo-4-hydroxy-benzoyl)-2- ethyl-benzofuran-6-sulfonicacid-(4-(thiazol-2-ylsulfamyl)-phenyl)-amide; EGFR, EGF receptor; pNPP, p-nitrophenylphosphate.


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