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Origin and functional evolution of FGF receptors

(Rebscher et al., 2009; Rudolf et al., 2012; Hasse et al., 2014; Suryawanshi et al., 2020)

FGFRs are metazoan-specific receptor tyrosine kinases. They are essential for migration of mesodermal cells, for morphogenesis of branched structures and boundary formation in ecto- and mesodermal tissues. Following interaction with, mostly soluble, FGFs and heparan sulfate proteoglycans of the ECM, FGFRs dimerize and become activated by autophosphorylation. This step allows coupling to either the Rho-Rock-myosin II, the Ras-MAPK or the PI-PKC and PI3-kinase downstream pathways.

FGFRs evolved early during metazoan evolution (Rebscher et al., 2009). The data indicate that multidomain FGFRs evolved from an already complex ancestral molecule, in which six of the seven domains were already present (Fig. 1).

In order to investigate the functional conservation of FGFRs, we expressed the Hydra kringelchen FGFR (see below) in heterologous test systems like cell culture or, in cooperation with R. Renkawitz-Pohl, Marburg, in Drosophila (Rudolf et al., 2012). Drosophila possesses two FGFRs, Breathless (Btl) and Heartless (Htl) and mutants are lethal since either the tracheal system fails to develop or mesodermal cells fail to migrate and the heart does not form. Drosophila development is not affected by overexpression of the Hydra protein and the fly integrates Kringelchen correctly into the cell membrane. However, only the very early steps of mesodermal cell spreading were rescued by the Hydra FGFR in FGFR-mutant flies. Whether the Hydra FGFR is able to use the fly docking protein Dof, therefore, remains an open question.

In transgenic Hydra, one of the two FGFRs, Kringelchen, is clearly responsible for proper bud detachment (Hasse et al., 2014). In the dominant-negative mutant, buds fail to detach, while ectopic expression causes tissue separation. Bud evagination is not affected and therewith, the mechanism of action is different in this respect from the one in vertebrates where FGFR induces evagination and growth of limbs as a comparable process.

Interestingly, both Hydra FGFRs might couple to downstream cascades without using homologs of the essential docking proteins Dof in fly and Frs2 in vertebrates (Suryawanshi et al., 2020). Instead, gene expression data suggest that direct coupling to adapter proteins (Grb2 and Crkl) is more likely to target the Rho-GEF Sos, the tyrosine phosphatase Shp2 as well as one of the Hydra Sprouty proteins.