Protein kinase A signalling in Schistosoma mansoni cercariae and schistosomules

Hirst, Natasha L.; Lawton, Scott P; Walker, Anthony J.

doi:10.1016/j.ijpara.2015.12.001

Cited by 20 publications

(17 citation statements)

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“…We have previously employed such antibodies to functionally study protein kinase (e.g. PKC [14,47], MAPK [14,57,72], Akt [15], PKA [13,50]) signalling in S. mansoni and the phosphorylation site data presented here offers further opportunity to either validate additional existing anti-phospho antibodies/develop new antibodies to facilitate the study of protein kinase signalling in schistosomes in various contexts (developmental, host-parasite interplay etc). Protein kinases also represent excellent drug targets and a growing number of protein kinase inhibitors have been approved for use in humans [77]; thus, protein kinases of schistosomes are being considered as possible therapeutic targets including through drug repurposing [5,20,21].…”

Section: Discussionmentioning

confidence: 99%

“…The five protein kinases selected for interactome phosphorylation analysis were all TDR targets: Smp_093930 (EGFR; SER), Smp_128480 (PKCβ), Smp_047900 (ERK2), Smp_073930.2 (Akt), Smp_152330 (PKA), with associated Target IDs 282997, 290399, 283994, 324234, and 286928, respectively. These protein kinases were also chosen due to their recognised importance to schistosome biology, particularly in relation to host-parasite interactions [13,45,46], reproduction and development [14,47,48], glucose uptake [15], and motor activity and survival [49,50]. Analysis of the five networks revealed a high proportion of phosphorylated partners within each interactome.…”

Section: Discussionmentioning

confidence: 99%

“…japonicum, or obstructive and inflammatory disease in the urinary system in the case of S. haematobium [7]. The parasite (both larval and adult stages) is highly adapted to thrive in the human host; it feeds on host blood and possesses a complex tegument thought to play an important role in host immune evasion, osmoregulation, excretion and glucose uptake [8][9][10][11], and can respond to host growth factors and other signalling molecules [12][13][14][15]. Ultimately, the exquisite biology of the schistosome underpins its fecundity and longevity-surviving on average for five to 10 years [16], but possibly up to 30 years [7]-in the human host.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Although helminth parasites cause enormous suffering worldwide we know little of how protein phosphorylation, one of the most important post-translational modifications used for molecular signalling, regulates their homeostasis and function. This is particularly the case for schistosomes. Herein, we report a deep phosphoproteome exploration of adult Schistosoma mansoni, providing one of the richest phosphoprotein resources for any parasite so far, and employ the data to build the first parasite-specific kinomic array. Complementary phosphopeptide enrichment strategies were used to detect 15,844 unique phosphopeptides mapping to 3,176 proteins. The phosphoproteins were predicted to be involved in a wide range of biological processes and phosphoprotein interactome analysis revealed 55 highly interconnected clusters including those enriched with ribosome, proteasome, phagosome, spliceosome, glycolysis, and signalling proteins. 93 distinct phosphorylation motifs were identified, with 67 providing a 'footprint' of protein kinase activity; CaMKII, PKA and CK1/2 were highly represented supporting their central importance to schistosome function. Within the kinome, 808 phosphorylation sites were matched to 136 protein kinases, and 68 sites within 37 activation loops were discovered. Analysis of putative protein kinase-phosphoprotein interactions revealed canonical networks but also novel interactions between signalling partners. Kinomic array analysis of male and female adult worm extracts revealed high phosphorylation of transformation:transcription domain associated protein by both sexes, and CDK and AMPK peptides by females. Moreover, eight peptides including protein phosphatase 2C gamma, Akt, Rho2 GTPase, SmTK4, and the insulin receptor were more highly phosphorylated by female extracts, highlighting their possible importance to female worm function. We envision that these findings, tools and methodology will help drive new research into the functional biology of schistosomes and other helminth parasites, and support efforts to develop new therapeutics for their control.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…The diversity of effects is presumably enabled through the existence of multiple 5-HT receptors [ 20 ]. Evidence has accumulated that 5-HT receptors can signal through cyclic AMP (cAMP) [ 7 , 21 ] and PKA [ 22 ] although other second messenger pathway s may also be involved [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Unique pharmacological properties of serotoninergic G-protein coupled receptors from cestodes

et al. 2018

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BackgroundCestodes are a diverse group of parasites, some of them being agents of neglected diseases. In cestodes, little is known about the functional properties of G protein coupled receptors (GPCRs) which have proved to be highly druggable targets in other organisms. Notably, serotoninergic G-protein coupled receptors (5-HT GPCRs) play major roles in key functions like movement, development and reproduction in parasites.Methodology/Principal findingsThree 5-HT GPCRs from Echinococcus granulosus and Mesocestoides corti were cloned, sequenced, bioinformatically analyzed and functionally characterized. Multiple sequence alignment with other GPCRs showed the presence of seven transmembrane segments and conserved motifs but interesting differences were also observed. Phylogenetic analysis grouped these new sequences within the 5-HT7 clade of GPCRs. Molecular modeling showed a striking resemblance in the spatial localization of key residues with their mammalian counterparts. Expression analysis using available RNAseq data showed that both E. granulosus sequences are expressed in larval and adult stages. Localization studies performed in E. granulosus larvae with a fluorescent probe produced a punctiform pattern concentrated in suckers. E. granulosus and M. corti larvae showed an increase in motility in response to serotonin. Heterologous expression revealed elevated levels of cAMP production in response to 5-HT and two of the GPCRs showed extremely high sensitivity to 5-HT (picomolar range). While each of these GPCRs was activated by 5-HT, they exhibit distinct pharmacological properties (5-HT sensitivity, differential responsiveness to ligands).Conclusions/SignificanceThese data provide the first functional report of GPCRs in parasitic cestodes. The serotoninergic GPCRs characterized here may represent novel druggable targets for antiparasitic intervention.

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“…Furthermore, in S. mansoni the linker region of common mediator (Co-)Smad4 contains three ERK phosphorylation motifs opening the possibility that ERK could restrict interaction of Smad4 with receptor activated (R-)Smad2 to modify TGFβ-mediated outcomes 36 41 . Activated protein kinase A (PKA) has also recently been shown to localise to multiple structures in S. mansoni somules including the tegument and PKA activation in somules was upregulated by human serotonin and dopamine but was supressed by neuropeptide Y 42 . Perhaps not surprisingly, PKA is known to influence ERK 43 and PKC 44 signalling in other systems through cross-talk to allow dynamic and specific control of signalling dependent upon input signal.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of host-parasite cell signalling in Schistosoma mansoni during early development

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Elbeyioglu

Kirk

et al. 2016

Sci Rep

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During infection of their human definitive host, schistosomes transform rapidly from free-swimming infective cercariae in freshwater to endoparasitic schistosomules. The ‘somules’ next migrate within the skin to access the vasculature and are surrounded by host molecules that might activate intracellular pathways that influence somule survival, development and/or behaviour. However, such ‘transactivation’ by host factors in schistosomes is not well defined. In the present study, we have characterized and functionally localized the dynamics of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) activation during early somule development in vitro and demonstrate activation of these protein kinases by human epidermal growth factor, insulin, and insulin-like growth factor I, particularly at the parasite surface. Further, we provide evidence that support the existence of specialized signalling domains called lipid rafts in schistosomes and propose that correct signalling to ERK requires proper raft organization. Finally, we show that modulation of PKC and ERK activities in somules affects motility and reduces somule survival. Thus, PKC and ERK are important mediators of host-ligand regulated transactivation events in schistosomes, and represent potential targets for anti-schistosome therapy aimed at reducing parasite survival in the human host.

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Protein kinase A signalling in Schistosoma mansoni cercariae and schistosomules

Cited by 20 publications

References 71 publications

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

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

Unique pharmacological properties of serotoninergic G-protein coupled receptors from cestodes

Molecular characterization of host-parasite cell signalling in Schistosoma mansoni during early development

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