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Updated: Aug 5, 2025
Microbead Implantation in the Zebrafish Embryo
Published on: July 30, 2015
FRS2-independent GRB2 interaction with FGFR2 is not required for embryonic development
James F Clark1, Philippe Soriano1
1Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Abstract:
FGF activation is known to engage canonical signals, including ERK/MAPK and PI3K/AKT, through various effectors including FRS2 and GRB2. Fgfr2 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 if this interaction provides functionality beyond canonical signaling, we generated mutant mice harboring a C-terminal truncation (T). We found that Fgfr2 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 mutants did not exhibit significantly more severe phenotypes. We therefore conclude that, while GRB2 can bind to FGFR2 independently of FRS2, this binding does not have a critical role in development or homeostasis.
Insights
Fibroblast Growth Factor Receptor 2 (FGFR2) C-terminal binding to GRB2 is not essential for mouse development or homeostasis. This non-canonical interaction does not appear to play a critical role in FGFR2 signaling pathways.
Area of Science:
- Cell Biology
- Molecular Biology
- Developmental Biology
Background:
- Fibroblast Growth Factor (FGF) signaling is crucial for cellular processes, primarily mediated by canonical pathways like ERK/MAPK and PI3K/AKT.
- FGFR2 mutations affecting canonical signaling result in mild phenotypes, contrasting with embryonic lethal mutations, suggesting alternative signaling mechanisms.
Approach:
- Generated mutant mice with a C-terminal truncation (T) in FGFR2 to investigate GRB2 binding independently of FRS2.
- Assessed the developmental and homeostatic roles of this non-canonical GRB2-FGFR2 interaction in mice.
- Introduced the truncation mutation onto a sensitized FCPG background to identify potential synergistic effects.
Key Points:
- Mice with the FGFR2 C-terminal truncation (Fgfr2 T) were viable and showed no discernible phenotype.
- GRB2 binding to the FGFR2 C-terminus is not required for normal development or adult homeostasis.
- The T mutation did not significantly exacerbate phenotypes on the sensitized FCPG background.
Conclusions:
- The non-canonical interaction between GRB2 and the FGFR2 C-terminus, independent of FRS2, does not play a critical role in mouse development or homeostasis.
- This finding clarifies the functional significance of alternative signaling pathways in FGF receptor signaling.
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