Human Transforming Growth Factor-β Activates a Receptor Serine/Threonine Kinase from the Intravascular ParasiteSchistosoma mansoni

Abstract

The biology of the helminth parasite Schistosoma mansoni is closely integrated with that of its mammalian host. SmRK1, a divergent type I transforming growth factor-␤ (TGF-␤) receptor of unknown ligand specificity, was previously identified as a candidate for a receptor that allows schistosomes to respond to hostderived growth factors. The TGF-␤ family includes activin, bone morphogenetic proteins (BMPs), and TGF-␤, all of which can play crucial roles in metazoan development. The downstream signaling protein of receptors that respond to TGF-␤ and activin is Smad2, whereas the receptors that respond to BMPs signal via Smad1. When a constitutively active mutant of SmRK1 was overexpressed with either schistosome Smad1 (SmSmad1) or SmSmad2, a receptor-dependent modulation of SmSmad phosphorylation and luciferase reporter activity occurred only with SmSmad2. To evaluate potential ligand activators of SmRK1, a chimeric receptor containing the extracellular domain of SmRK1 joined to the intracellular domain of the human type I TGF-␤ receptor was used. The chimeric receptor bound radiolabeled TGF-␤ and could activate a luciferase reporter gene in response to both TGF-␤1 and TGF-␤3 but not BMP7. Confirmatory results were obtained using full-length SmRK1. These experiments implicate TGF-␤ as a ligand for SmRK1 and as a potential host-derived regulator of parasite growth and development.

Helminth Infection and Type 1 Diabetes

“…These findings are mirrored in the human clinical setting, where studies of HIVpositive patients in regions endemic for S. mansoni revealed that fecal egg counts, but not infection intensity, were negatively correlated with CD4 + T cell counts [23]. Further supporting the coevolution of S. mansoni with the mammalian immune system, evidence exists that adult worms can sense the human regulatory cytokine, transforming growth factor beta (TGF-β), and that stimulation with TGF-β induces expression of genes linked to sexual maturation and malefemale interaction and may modulate embryonic development [24][25][26][27]. S. mansoni has thus evolved not only to detect mediators of host immunity, but also to use these signals in its own program of maturation and reproduction.…”

Growth factor receptors in helminth parasites: Signalling and host–parasite relationships

“…1) and shown to be expressed at the surface of the parasite following its entry into the mammalian host [13]. Using a heterologous expression system, SmTbR1 was shown to interact with human TbRII and to activate Smad2 signalling molecules in response to human TGF-b [14]. Two R-Smads (SmSmad1 and SmSmad2) as well as a Co-Smad (SmSmad4) have been identified as downstream partners of SmTbR1 [15][16][17].…”

Protein tyrosine kinases in Schistosoma mansoni

“…Both Smads (SmSmad1 and SmSmad2) and SmRK1 are found in the same developmental stages (lung stage and adult parasites). SmSmad2 interacts with SmRK1, while SmSmad4 interacts with SmSmad1 and SmSmad2, besides phosphorylating Erk1/2 (kinase regulated by extracellular signal) (Beall et al 2000, Beall & Pearce 2001, Osman et al 2001. FKBP12 influences a variety of signal transduction pathways that regulate cell division, differentiation, and ion homeostasis.…”