Molecular Cloning and Characterization of a P38-Like Mitogen-Activated Protein Kinase from Echinococcus granulosus

Abstract

Cystic echinococcosis (CE) treatment urgently requires a novel drug. The p38 mitogen-activated protein kinases (MAPKs) are a family of Ser/Thr protein kinases, but still have to be characterized in Echinococcus granulosus. We identified a 1,107 bp cDNA encoding a 368 amino acid MAPK protein (Egp38) in E. granulosus. Egp38 exhibits 2 distinguishing features of p38-like kinases: a highly conserved T-X-Y motif and an activation loop segment. Structural homology modeling indicated a conserved structure among Egp38, EmMPK2, and H. sapiens p38α, implying a common binding mechanism for the ligand domain and downstream signal transduction processing similar to that described for p38α. Egp38 and its phosphorylated form are expressed in the E. granulosus larval stages vesicle and protoscolices during intermediate host infection of an intermediate host. Treatment of in vitro cultivated protoscolices with the p38-MAPK inhibitor ML3403 effectively suppressed Egp38 activity and led to significant protoscolices death within 5 days. Treatment of in vitro-cultivated protoscolices with TGF-β1 effectively induced Egp38 phosphorylation. In summary, the MAPK, Egp38, was identified in E. granulosus, as an anti-CE drug target and participates in the interplay between the host and E. granulosus via human TGF-β1.

Identification of Functional MKK3/6 and MEK1/2 Homologs from Echinococcus granulosus and Investigation of Protoscolecidal Activity of Mitogen-Activated Protein Kinase Signaling Pathway Inhibitors In Vitro and In Vivo

“…As parasitic helminths, the various species of E. granulosus sensu lato depend on host molecular signals for their growth and development (5)(6)(7). The microenvironment for Echinococcus spp.…”

Transcriptome analysis uncovers the key pathways and candidate genes related to the treatment of Echinococcus granulosus protoscoleces with the repurposed drug pyronaridine

“…According to KEGG enrichment analysis, the MAPK pathway comes in second in the top-changed pathways affected by PND. In the last decade, a few components of the MAPK pathway have been identified in E. granulosus , including Eg p38, Eg ERK, Eg MKK1 and Eg MKK2 [ 21 – 23 ]. Meanwhile, some MAPK inhibitors (e.g., sorafenib, U0126, SB202190) were found to effectively kill E. granulosus in vitro and/or in vivo [ 21 , 24 , 25 ], proving that the key kinases could be used as potential targets for anti-CE drug development.…”

Echinococcosis: Recent Advancements in OMIC Technologies

“…Certain proteins may be effective as chemotherapeutic targets along with enhanced immunodiagnosis or immunotherapy because they function as chemical mediators for networking between CE and its mammal host (Zheng et al 2013;Tsai et al 2013). For example, genes of a germinal layer of the parasite prepare polypeptides and proteins that can be used in the development of vaccines such as GPCRs, MAPK, neuro-peptides, and ion channel (Lu et al 2016;Lin et al 2011;Gelmedin et al 2010;Gelmedin et al 2008). Both E. multilocularis and E. granulosus protoscoleces contain hormone-and cytokine-activated pathways, therefore, it is of the utmost importance that host components activate or deactivate them (Yang et al 2017;Koziol et al 2016a;Hemer et al 2014;Lu et al 2016;Gelmedin et al 2008;Gelmedin et al 2010;Hemer et al 2014;Zhang et al 2014;Brehm and Spiliotis 2008;Konrad et al 2003;Brehm 2010;Spiliotis et al 2006;Spiliotis et al 2005;Zavala-Gongora et al 2003;Spiliotis et al 2003).…”

“…For example, genes of a germinal layer of the parasite prepare polypeptides and proteins that can be used in the development of vaccines such as GPCRs, MAPK, neuro-peptides, and ion channel (Lu et al 2016;Lin et al 2011;Gelmedin et al 2010;Gelmedin et al 2008). Both E. multilocularis and E. granulosus protoscoleces contain hormone-and cytokine-activated pathways, therefore, it is of the utmost importance that host components activate or deactivate them (Yang et al 2017;Koziol et al 2016a;Hemer et al 2014;Lu et al 2016;Gelmedin et al 2008;Gelmedin et al 2010;Hemer et al 2014;Zhang et al 2014;Brehm and Spiliotis 2008;Konrad et al 2003;Brehm 2010;Spiliotis et al 2006;Spiliotis et al 2005;Zavala-Gongora et al 2003;Spiliotis et al 2003). If we compare the genetic structure of both parasites, it will become obvious that parasites have a high level of similarity, revealing that many compounds are produced by both parasites and can be aimed at creating new therapies.…”