Abstract
Across the Bilateria, FGF/FGFR signaling is critical for normal development, and in both Drosophila and vertebrates, docking proteins are required to connect activated FGFRs with downstream pathways. While vertebrates use Frs2 to dock FGFR to the RAS/MAPK or PI3K pathways, the unrelated protein, downstream of FGFR (Dof/stumps/heartbroken), fulfills the corresponding function in Drosophila. To better understand the evolution of the signaling pathway downstream of FGFR, the available sequence databases were screened to identify Frs2, Dof, and other key pathway components in phyla that diverged early in animal evolution. While Frs2 homologues were detected only in members of the Bilateria, canonical Dof sequences (containing Dof, ankyrin, and SH2/SH3 domains) were present in cnidarians as well as bilaterians (but not in other animals or holozoans), correlating with the appearance of FGFR. Although these data suggested that Dof coupling might be ancestral, gene expression analysis in the cnidarian Hydra revealed that Dof is not upregulated in the zone of strong FGFRa and FGFRb expression at the bud base, where FGFR signaling controls detachment. In contrast, transcripts encoding other, known elements of FGFR signaling in Bilateria, namely the FGFR adaptors Grb2 and Crkl, which are acting downstream of Dof (and Frs2), as well as the guanyl nucleotide exchange factor Sos, and the tyrosine phosphatase Csw/Shp2, were strongly upregulated at the bud base. Our expression analysis, thus, identified transcriptional upregulation of known elements of FGFR signaling at the Hydra bud base indicating a highly conserved toolkit. Lack of transcriptional Dof upregulation raises the interesting question, whether Hydra FGFR signaling requires either of the docking proteins known from Bilateria.
Highlights
Across the Bilateria, fibroblast growth factor receptors (FGFR) and their ligands control embryonic as well as adult morphogenesis
The receptor tyrosine kinase (RTK) superfamily has earlier origins, the FGF/FGFR signaling system is thought to have evolved in Ureumetazoa, the last common ancestor of Cnidaria and Bilateria (Babonis and Martindale 2017; Bertrand et al 2014; Lange et al 2014; Oulion et al 2012; Rebscher et al 2009)
The FGFR docking proteins of vertebrates, Frs2 homologues, typically, carry an N-terminal myristoylation site (Fig. 1), which ensures their modification by a lipid anchor and constitutive localization to the plasma membrane
Summary
Across the Bilateria, fibroblast growth factor receptors (FGFR) and their ligands control embryonic as well as adult morphogenesis. In Drosophila, Dof (downstream of FGFR, known as stumps or heartbroken), is essential for FGFR signaling and connects the heartless and breathless FGFRs to the RAS/MAPK or PI3 kinase signaling pathways (Csiszar et al 2010; Michelson et al 1998; Muha and Muller 2013; Vincent et al 1998) In both cases, the activated FGFR dimer phosphorylates conserved tyrosines in the docking proteins and generates secondary binding sites for the intracellular adapters Grb (Kouhara et al 1997), Crk and Crkl (Birge et al 2009) as well as the tyrosine phosphatase Shp2/Csw In the nematode C. elegans, Grb is the only known FGFR docking protein: Frs has no FGFR docking function and the genome does not encode a Dof homologue (Lo et al 2010)
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