Conservation of Epidermal Growth Factor Receptor Function in the Human Parasitic Helminth Schistosoma mansoni

Abstract

The epidermal growth factor receptor (EGF-R) plays an important role in development and cell differentiation, and homologues of EGF-R have been identified in a broad range of vertebrate and invertebrate organisms. This work concerns the functional characterization of SER, the EGF-R-like molecule previously identified in the helminth parasite Schistosoma mansoni The epidermal growth factor receptor (EGF-R) 1 is a major key mediator of cell communication during animal development and homeostasis. EGF-R was the first receptor tyrosine kinase to be cloned (1), and its structure and activation pathways have been studied extensively. EGF-R represents the archetype of receptor tyrosine kinase with an extracellular ligand-binding part with two cysteine-rich repeats and an intracellular domain containing tyrosine kinase activity (2). In mammals, four isoforms of EGF-R have been characterized (EGF-R/ErbB-1, HER2/ErbB-2, HER3/ErbB-3, and HER4/ ErbB-4), and a number of different ligands, including epidermal growth factor (EGF)-like molecules, can selectively bind each isoform (3). Ligand binding activates the receptor by inducing the formation of homo-heterodimers. Dimerization triggers trans-phosphorylation and subsequent autophosphorylation of receptor molecules on tyrosine residues that provide docking sites for diverse effector and adaptor proteins. These partners (Grb2/Sos, p85-PI3K, PLC␥, and JAK) are active in different signal transduction cascades, such as the mitogenactivated protein kinase (MAPK), phosphoinositol 3-kinase, antiapoptotic kinase Akt, and several transcriptional regulatory pathways (reviewed in Ref. 4). Different homodimer-heterodimer combinations formed by EGF-R family members drive a complex signaling network within the MAPK pathway. The ERK pathway is the most recurrent and is mainly responsible for the mitogenic action of EGF receptors. Dysregulation of EGF-R signaling is therefore strongly oncogenic, and the direct implication of EGF-R isoforms in various cancers has been widely demonstrated. For this reason, EGF-R currently represents one of the major drug targets in human cancer therapy (5).In invertebrates, EGF-R isoforms appeared to be expressed in more limited numbers. A single isoform has been characterized in Caenorhabditis elegans (LET-23) (6) as well as in Drosophila melanogaster (DER) (7,8). A single cognate ligand (LIN-3) would be present in the worm (9), and four distinct cognate ligands (Vein, Gurken, Spitz, and Argos) would be present in the fly (10). These observations indicated that the EGF-R signaling module has grown in complexity from invertebrates to mammals. However, except for C. elegans and D. melanogaster models, few data are available at present about the role of the EGF-R family in invertebrate development.SER, the Schistosoma mansoni EGF-R homologue, is one of the three receptor tyrosine kinases that have been characterized in this trematode parasite (11,12). SER is present predominantly in schistosome muscles, suggesting that it could

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

“…Similar observations have been made in the S. mansoni model, incubation of parasites with human EGF increasing protein and DNA synthesis as well as protein phosphorylation in larval stages [38]. Therefore, as already proposed for the growth factor TGF-b, a potential role of EGF and of its transduction cascades in the regulation of host-parasite relationships can be considered.…”

“…Recent studies on the functional activity of EGF-R in S. mansoni confirmed the conservation of EGF signalling in this parasite [38]. The epidermal growth factor receptor (EGF-R) is a major key mediator of cell communication during animal development and homeostasis.…”

Specific tyrosine phosphorylation induced in Schistosoma mansoni miracidia by haemolymph from schistosome susceptible, but not resistant, Biomphalaria glabrata

“…Such phosphorylation has been shown to be modulated in host-parasite systems during processes as diverse as host cell invasion (Neira et al 2002) and growth factor cross-talk (Vicogne et al 2004), and in response to other host-derived molecular cues Marcila et al 2004). Although relatively few signalling enzymes have been characterized in schistosomes, recent studies have identified several receptor and nonreceptor PTKs in S. mansoni.…”

Regulation of protein phosphatase type 1 and cell cycle progression by PfLRR1, a novel leucine‐rich repeat protein of the human malaria parasite Plasmodium falciparum

“…Preparations of Xenopus oocytes and microinjection experiments were performed as previously described (Vicogne et al, 2004). In each assay, 20 oocytes removed from at least two to three different animals were microinjected with different concentrations of OA, sera anti-PP1 antibodies, PfLRR1 cRNA or Grb2 P49L cRNA.…”