Figure 3.

Signaling pathways that drive differentiation when trypanosomes enter the tsetse midgut. Citrate-cis aconitate (CCA) is transported by cell membrane PAD proteins (a), this being favored under cold shock conditions. CCA inhibits the activity of the differentiation inhibitor, TbPTP1 (b) a tyrosine phosphatase whose activity is normally enhanced by its substrate, TbPIP39. When TbPTP1 is inhibited, TbPIP39 becomes phosphorylated and more active (c). TbPIP39 can relocate to the glycosome (though this is not dependent upon its phosphorylation) whereupon it acts on unidentified substrates to promote differentiation (d). The same signaling pathway is stimulated by exposure of stumpy forms to mild acid conditions (pH 5.5 for 2 h) (e), which also generates phosphorylated TbPIP39. Exposure of stumpy forms to proteases at the cell surface (f) also stimulates differentiation, but this does not involve TbPTP1 or TbPIP39 and operates through an uncharacterized pathway (g) that may or may not involve the glycosome. It is also not necessary for differentiation in the midgut of tsetse. A reduction of environmental glucose (h) has also been suggested to initiate differentiation, but reducing medium glucose 20-fold, or using the transport inhibitor phloretin, does not cause the differentiation of stumpy forms to procyclic forms.