Abstract
Subtype R3 phosphotyrosine phosphatase receptors (R3 RPTPs) are single-spanning membrane proteins characterized by a unique modular composition of extracellular fibronectin repeats and a single cytoplasmatic protein tyrosine phosphatase (PTP) domain. Vertebrate R3 RPTPs consist of five members: PTPRB, PTPRJ, PTPRH and PTPRO, which dephosphorylate tyrosine residues, and PTPRQ, which dephosphorylates phophoinositides. R3 RPTPs are considered novel therapeutic targets in several pathologies such as ear diseases, nephrotic syndromes and cancer. R3 RPTP vertebrate receptors, as well as their known invertebrate counterparts from animal models: PTP52F, PTP10D and PTP4e from the fruitfly Drosophila melanogaster and F44G4.8/DEP-1 from the nematode Caenorhabditis elegans, participate in the regulation of cellular activities including cell growth and differentiation. Despite sharing structural and functional properties, the evolutionary relationships between vertebrate and invertebrate R3 RPTPs are not fully understood. Here we gathered R3 RPTPs from organisms covering a broad evolutionary distance, annotated their structure and analyzed their phylogenetic relationships. We show that R3 RPTPs (i) have probably originated in the common ancestor of animals (metazoans), (ii) are variants of a single ancestral gene in protostomes (arthropods, annelids and nematodes); (iii) a likely duplication of this ancestral gene in invertebrate deuterostomes (echinodermes, hemichordates and tunicates) generated the precursors of PTPRQ and PTPRB genes, and (iv) R3 RPTP groups are monophyletic in vertebrates and have specific conserved structural characteristics. These findings could have implications for the interpretation of past studies and provide a framework for future studies and functional analysis of this important family of proteins.
Highlights
Phosphotyrosine phosphatases, along with protein tyrosine kinases, regulate the levels of phosphotyrosine modification in cells [1, 2]
Despite extensive searches of genome and protein databases we could not find any orthologue of R3 Receptor phosphotyrosine phosphatases (RPTPs) genes in amphioxus (Branchiostoma floridae) another deuterostome, or in other organisms that diverged before the split of duterostomes and protostomes: cinidarians (Nematostella vectensis, Hydra vulgaris, and Hydra magnipapillata) and placozoans (Trichoplax adhaerens)
The results of our searches placed the probable origin of R3 RPTPs in the common ancestor of animals since no R3 subtype sequences were present in organisms which diverged early than sponges, including Monosiga and Capsaspora, the closest protists to the animal kingdom [33,34]
Summary
Phosphotyrosine phosphatases, along with protein tyrosine kinases, regulate the levels of phosphotyrosine modification in cells [1, 2]. Phosphotyrosine phosphatases play a major role in tuning cell function, and are considered therapeutic targets since their deregulation leads to health disorders including cancer [2,3,4,5].
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