Exploring the function of protein kinases in schistosomes: perspectives from the laboratory and from comparative genomics

Abstract

Eukaryotic protein kinases are well conserved through evolution. The genome of Schistosoma mansoni, which causes intestinal schistosomiasis, encodes over 250 putative protein kinases with all of the main eukaryotic groups represented. However, unraveling functional roles for these kinases is a considerable endeavor, particularly as protein kinases regulate multiple and sometimes overlapping cell and tissue functions in organisms. In this article, elucidating protein kinase signal transduction and function in schistosomes is considered from the perspective of the state-of-the-art methodologies used and comparative organismal biology, with a focus on current advances and future directions. Using the free-living nematode Caenorhabditis elegans as a comparator we predict roles for various schistosome protein kinases in processes vital for host invasion and successful parasitism such as sensory behavior, growth and development. It is anticipated that the characterization of schistosome protein kinases in the context of parasite function will catalyze cutting edge research into host-parasite interactions and will reveal new targets for developing drug interventions against human schistosomiasis.

Deep phosphoproteome analysis of Schistosoma mansoni leads development of a kinomic array that highlights sex-biased differences in adult worm protein phosphorylation

“…A similar number (261) are reported in S. haematobium [21]. In schistosomes, several protein kinases have been found to play important roles in a wide range of processes including development and behaviour of the larval stages, and reproductive development, pairing and survival of the adults (reviewed in [20,22]). However, despite the first schistosome (S. mansoni) genome being published in 2009 [23,24], we only have limited knowledge of protein phosphorylation events in these important parasites, with two separate studies on S. japonicum identifying 127 phosphopeptides in 92 proteins and 180 phosphopeptides in 140 proteins, respectively [25,26].…”

“…Based on substrate proteins of interest (phosphopeptides; see methods) and knowledge of their putative upstream kinases in S. mansoni, a 96-spot custom CelluSpots peptide array containing 15 mer peptides was built that was purposely biased towards cell signalling processes (S10 Table). The annotation of putative upstream kinases was based upon ScanSite and Phospho.ELM data, knowledge of comparative phosphorylation sites in signalling proteins, and our analysis of kinase/phosphorylation while investigating cell signalling in S. mansoni [14,15,22,50,56,57]. Some phosphorylation sites within the peptides (e.g.…”

Targeting kinases in Plasmodium and Schistosoma: Same goals, different challenges

“…RNAi and inhibition studies in S. mansoni unravelled the role of the catalytic subunit of SmPKA (SmPKA-C). PKA loss negatively influenced egg production and was lethal for adults in vitro [34] whereas PKA activation stimulated neuromuscular movement [35].…”

“…The S. mansoni homolog of p38 MAPK is involved in transition processes during larval development and in ciliary motion of miracidia [35]. For adult worms it was shown that SmJNK controls parasite maturation and survival, whereas SmERK has a function for ovary development and egg production [37].…”

Protein kinase A signalling in Schistosoma mansoni cercariae and schistosomules

“…However, of the two tools, 366 pkaPS predicted many more potential sites (551) type II-alpha regulatory subunit (Smp_079010) and calmodulin (Smp_026560.2) were 453 also recently detected in the tegument fraction of somules using proteomic approaches 454 (Sotillo et al, 2015). Moreover, the high confidence interacting protein dataset included 455 four heat shock/DnaJ-like proteins/factors, four protein kinases, nine leucine-rich repeat 456 containing proteins, three Shoc-2 proteins, and other signalling proteins such as TGF-β 457 family member, and a Ras GTP exchange factor and Ras suppressor protein 1 that would 458 be important to ERK signalling in the parasite (Ressurreição et al, 2014) …”