Dissous C et al. (2014), Venus kinase receptors: prospects in signaling ...

ECB-ART-50055

Front Endocrinol (Lausanne) 2014 May 13;5:72. doi: 10.3389/fendo.2014.00072.

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Venus kinase receptors: prospects in signaling and biological functions of these invertebrate kinases.

Dissous C , Morel M , Vanderstraete M .

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Venus kinase receptors (VKRs) form a family of invertebrate receptor tyrosine kinases (RTKs) initially discovered in the parasitic platyhelminth Schistosoma mansoni. VKRs are single transmembrane receptors that contain an extracellular venus fly trap structure similar to the ligand-binding domain of G protein-coupled receptors of class C, and an intracellular tyrosine kinase domain close to that of insulin receptors. VKRs are found in a large variety of invertebrates from cnidarians to echinoderms and are highly expressed in larval stages and in gonads, suggesting a role of these proteins in embryonic and larval development as well as in reproduction. VKR gene silencing could demonstrate the function of these receptors in oogenesis as well as in spermatogenesis in S. mansoni. VKRs are activated by amino acids and are highly responsive to arginine. As many other RTKs, they form dimers when activated by ligands and induce intracellular pathways involved in protein synthesis and cellular growth, such as MAPK and PI3K/Akt/S6K pathways. VKRs are not present in vertebrates or in some invertebrate species. Questions remain open about the origin of this little-known RTK family in evolution and its role in emergence and specialization of Metazoa. What is the meaning of maintenance or loss of VKR in some phyla or species in terms of development and physiological functions? The presence of VKRs in invertebrates of economical and medical importance, such as pests, vectors of pathogens, and platyhelminth parasites, and the implication of these RTKs in gametogenesis and reproduction processes are valuable reasons to consider VKRs as interesting targets in new programs for eradication/control of pests and infectious diseases, with the main advantage in the case of parasite targeting that VKR counterparts are absent from the vertebrate host kinase panel.

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	Figure 1. Scheme of the distribution of VKR in animal phyla. VKR genes are present and expressed in Cnidaria, Arthropoda, Platyhelminths, Annelida, Mollusca, Hemichordata, and Echinodermata phyla. They were not found in the genomes of chordates and nematodes. Dashed lines indicate that the presence of VKR is speculative in these phyla due to the lack of genomic data. However, putative RTKs similar to VKR have been already detected in the choanoflagellates Monosiga brevicollis (18) and Salpingoeca rosetta (19).
	Figure 2. Structure and activation of VKR. VKR is composed of an intracellular TK domain similar to that of insulin receptor linked by a unique transmembrane domain to an extracellular moiety containing a venus fly trap (VFT) module. VFT domains are formed by two lobes separated by a highly flexible cleft, allowing the binding of a small molecule. VFT module of VKR was shown to bind amino acids and to have a high affinity for l-arginine. As many other RTKs, VKR is active as a dimer. Receptor dimerization occurs in the presence of l-Arg and leads to kinase activation, receptor autophosphorylation, and signal transduction.
	Figure 3. VKR signaling pathways. Closure of VFT extracellular domains upon binding of arginine ligand promotes and reinforces receptor dimerization inducing kinase activation and autophosphorylation of VKR. Phosphotyrosines can bind different partners for the transduction of conserved RTK signaling pathways, such as the PI3K/AKT/mTOR pathway involved in protein synthesis and the Ras/MAPK ERK pathway important for cell growth and proliferation. Moreover, activated VKRs could activate through the specific binding of Shb (SH2-containing protein), the alternative JNK pathway to contribute in concert with Rho1, MEK7, and PP2C to cytoskeleton rearrangement and oocyte maturation. Phosphorylation of AKT, p70S6K, ERK, and JNK (circled in red) was confirmed in VKR-expressing Xenopus oocytes (22).

References [+] :

Acher, Amino acid recognition by Venus flytrap domains is encoded in an 8-residue motif. 2005, Pubmed