Abstract
Fibroblast Growth Factor (FGF) Receptors (FGFRs) regulate essential biological processes, including embryogenesis, angiogenesis, cellular growth and memory-related long-term synaptic plasticity. Whereas canonical FGFRs depend exclusively on extracellular Immunoglobulin (Ig)-like domains for ligand binding, other receptor types, including members of the tropomyosin-receptor-kinase (Trk) family, use either Ig-like or Leucine-Rich Repeat (LRR) motifs, or both. Little is known, however, about the evolutionary events leading to the differential incorporation of LRR domains into Ig-containing tyrosine kinase receptors. Moreover, although FGFRs have been identified in many vertebrate species, few reports describe their existence in invertebrates. Information about the biological relevance of invertebrate FGFRs and evolutionary divergences between them and their vertebrate counterparts is therefore limited. Here, we characterized ApLRRTK, a neuronal cell-surface protein recently identified in Aplysia. We unveiled ApLRRTK as the first member of the FGFRs family deprived of Ig-like domains that instead contains extracellular LRR domains. We describe that ApLRRTK exhibits properties typical of canonical vertebrate FGFRs, including promotion of FGF activity, enhancement of neuritic outgrowth and signaling via MAPK and the transcription factor CREB. ApLRRTK also enhanced the synaptic efficiency of neurons known to mediate in vivo memory-related defensive behaviors. These data reveal a novel molecular regulator of neuronal function in invertebrates, provide the first evolutionary linkage between LRR proteins and FGFRs and unveil an unprecedented mechanism of FGFR gene diversification in primeval central nervous systems.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-014-1803-2) contains supplementary material, which is available to authorized users.
Highlights
Fibroblast Growth Factor Receptors (FGFRs) are cellsurface tyrosine kinase proteins that regulate a variety of essential biological functions, including embryological development, cellular growth, nervous system formation, adult neurogenesis and learning-related long-term synaptic plasticity (Itoh and Ornitz 2004; Itoh 2007; Coulier et al 1997; Lessmann 1998; Reuss and von Bohlen und Halbach O 2003; Stevens et al 2012; Zhao et al 2007)
ApLRRTK is a member of the FGFRs gene family
We performed a phylogenetic analysis for the conserved tyrosine kinase domain of ApLRRTK, FGFRs and other vertebrate and invertebrate tyrosine kinase-containing proteins indentified via BLAST search (“Materials and methods”)
Summary
Fibroblast Growth Factor Receptors (FGFRs) are cellsurface tyrosine kinase proteins that regulate a variety of essential biological functions, including embryological development, cellular growth, nervous system formation, adult neurogenesis and learning-related long-term synaptic plasticity (Itoh and Ornitz 2004; Itoh 2007; Coulier et al 1997; Lessmann 1998; Reuss and von Bohlen und Halbach O 2003; Stevens et al 2012; Zhao et al 2007). Combined molecular biological and functional electrophysiological studies corroborated the bioinformatics predictions and unveiled ApLRRTK as an enhancer of FGF signaling and a promoter of neuronal outgrowth and memory-related synaptic plasticity. These data reveal a completely novel molecular regulator in invertebrate nervous systems. We provide the first direct evolutionary link between LRR proteins and FGFRs, offering a novel molecular perspective for the evolutionary origins and diversification of FGFRs and LRR tyrosine kinase receptors
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