Direct binding of Grb2 SH3 domain to FGFR2 regulates SHP2 function

Area of Science:

• Cellular signaling
• Molecular biology
• Receptor tyrosine kinases

Background:

• The adaptor protein Grb2 is crucial for signal transduction in many receptor tyrosine kinase pathways, typically binding via its SH2 domain to phosphorylated tyrosine residues.
• Previous understanding suggested Grb2's SH2 domain mediates interactions with receptors or docking proteins.

Purpose of the Study:

• To investigate the interaction mechanism between Fibroblast Growth Factor Receptor 2 (FGFR2) and the Grb2 adaptor protein.
• To identify the specific domains and binding sites involved in this interaction.

Main Methods:

• Investigating receptor-Grb2 interactions using deletion mutants of FGFR2.
• Mapping the binding site on the C-terminus of FGFR2.
• Utilizing synthetic peptides to confirm binding affinity with Grb2.

Main Results:

• FGFR2 recruits Grb2 through its C-terminal SH3 domain, a previously undescribed interaction mode.
• The binding site was localized to the proline-rich C-terminus of FGFR2.
• Deletion of the terminal 10 amino acids of FGFR2 abolished Grb2 interaction.
• Synthetic peptides corresponding to the FGFR2 C-terminus exhibited low micromolar affinity for Grb2.
• This novel binding mechanism confers resistance to Shp2-mediated dephosphorylation of FGFR2.

Conclusions:

• FGFR2 employs a unique mechanism to bind Grb2 via its SH3 domain, distinct from canonical SH2 domain interactions.
• This alternative binding pathway plays a role in regulating receptor signaling and stability.
• The findings reveal a new layer of complexity in receptor tyrosine kinase signaling and Grb2 recruitment.