SmShb, the SH2-Containing Adaptor Protein B of Schistosoma mansoni Regulates Venus Kinase Receptor Signaling Pathways.

Marion Morel,Christoph G Grevelding,Colette Dissous,Steffen Hahnel,Mathieu Vanderstraete,Katia Cailliau

doi:10.1371/journal.pone.0163283

Abstract

Venus kinase receptors (VKRs) are invertebrate receptor tyrosine kinases (RTKs) formed by an extracellular Venus Fly Trap (VFT) ligand binding domain associated via a transmembrane domain with an intracellular tyrosine kinase (TK) domain. Schistosoma mansoni VKRs, SmVKR1 and SmVKR2, are both implicated in reproductive activities of the parasite. In this work, we show that the SH2 domain-containing protein SmShb is a partner of the phosphorylated form of SmVKR1. Expression of these proteins in Xenopus oocytes allowed us to demonstrate that the SH2 domain of SmShb interacts with the phosphotyrosine residue (pY979) located in the juxtamembrane region of SmVKR1. This interaction leads to phosphorylation of SmShb on tyrosines and promotes SmVKR1 signaling towards the JNK pathway. SmShb transcripts are expressed in all parasite stages and they were found in ovary and testes of adult worms, suggesting a possible colocalization of SmShb and SmVKR1 proteins. Silencing of SmShb in adult S. mansoni resulted in an accumulation of mature sperm in testes, indicating a possible role of SmShb in gametogenesis.

Highlights

Schistosomiasis is the second most important parasitic disease in the world with more than 240 million people infected in tropical and subtropical areas and is responsible for about 200 000 deaths per year [1]
A partial sequence of a protein referred in Genbank databases as hypothetical Src Homology-2 (SH2) domaincontaining protein (Genbank Accession Number CCD77461) was shown from Y2H S. mansoni library screening to interact with the tyrosine-phosphorylated intracellular domain of SmVKR1 in its active form (SmVKR1 Intracellular domains (ICD) YYRE) [11]
The SH2 domain-containing protein B (Shb) protein family is composed of Shb together with the three paralogs Shd, She and Shf proteins [31,32], and is distinct from the SHC, Grb2, Grb7 or Nck families, which are all composed of adaptor proteins with SH2 domains together with other variable motifs for protein-protein interaction

Summary

Introduction

Schistosomiasis is the second most important parasitic disease in the world with more than 240 million people infected in tropical and subtropical areas and is responsible for about 200 000 deaths per year [1]. Praziquantel (PZQ) is the drug used currently to cure schistosomiasis. It is safe, affordable and effective against the three major species of schistosomes infecting humans (Schistosoma mansoni, S. haematobium and S. japonicum) but its massive administration in endemic areas has increased the likelihood of emergence of PZQ-tolerant parasites [2,3,4,5]. There is a necessity to find new drugs and targets against schistosomes, and inhibiting parasite reproduction could be an excellent strategy to control both transmission and pathology of schistosomiasis.

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