FRS2-independent GRB2 interaction with FGFR2 is not required for embryonic development

FGF activation is known to engage canonical signals, including ERK/MAPK and PI3K/AKT, through various effectors including FRS2 and GRB2. Fgfr2(FCPG/FCPG) mutants that abrogate canonical intracellular signaling exhibit a range of mild phenotypes but are viable, in contrast to embryonic lethal Fgfr2(-/-) mutants. GRB2 has been reported to interact with FGFR2 through a non-traditional mechanism, by binding to the C-terminus of FGFR2 independently of FRS2 recruitment. To investigate whether this interaction provides functionality beyond canonical signaling, we generated mutant mice harboring a C-terminal truncation (T). We found that Fgfr2(T/T) mice are viable and have no distinguishable phenotype, indicating that GRB2 binding to the C-terminal end of FGFR2 is not required for development or adult homeostasis. We further introduced the T mutation on the sensitized FCPG background but found that Fgfr2(FCPGT/FCPGT) mutants did not exhibit significantly more severe phenotypes. We therefore conclude that, although GRB2 can bind to FGFR2 independently of FRS2, this binding does not have a critical role in development or homeostasis.

Automated summary

FGF activation engages canonical signals through various effectors, including FRS2 and GRB2. However, the interaction between GRB2 and FGFR2 is not required for development or adult homeostasis. Mutant mice lacking the C-terminal end of FGFR2 showed no distinguishable phenotype, indicating that GRB2 binding to FGFR2 is not critical for development or homeostasis.