title: Protein tyrosine phosphatase TbPTP1: A molecular switch controlling life cycle differentiation in trypanosomes.
abstract: 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.
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3JT, Scotland, UK.
authors.forename: Balázs
authors.initials: B
authors.lastname: Szöor
authors.forename: Jude
authors.initials: J
authors.lastname: Wilson
authors.forename: Helen
authors.initials: H
authors.lastname: McElhinney
authors.forename: Lydia
authors.initials: L
authors.lastname: Tabernero
authors.forename: Keith R
authors.initials: KR
authors.lastname: Matthews
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008018:Life Cycle Stages / Q000502:physiology*; D008969:Molecular Sequence Data; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D014346:Trypanosoma brucei brucei / Q000201:enzymology / Q000235:genetics / Q000254:growth & development*
chemical_list: D016877:Oxidants; D015800:Protozoan Proteins; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; D017027:Protein Tyrosine Phosphatases