Receptor-linked tyrosine kinases, such as the epidermal growth factor receptor (EGFR), are activated by extracellular ligands, such as the epidermal growth factor (EGF). Binding of EGF to the EGFR activates the tyrosine kinase activity of the cytoplasmic domain of the receptor. The EGFR becomes phosphorylated on tyrosine residues. Docking proteins such as GRB2 contain an SH2 domain that binds to the phosphotyrosine residues of the activated receptor. GRB2 binds to the guanine nucleotide exchange factor SOS by way of the two SH3 domains of GRB2. When the GRB2-SOS complex docks to phosphorylated EGFR, SOS becomes activated. Activated SOS then promotes the removal of GDP from a member of the Ras subfamily (most notably H-Ras or K-Ras). The Ras protein can then bind GTP and become active.
Apart from EGFR, other cell surface receptors that can activate this pathway via GRB2 include Trk A/B, Fibroblast growth factor receptor (FGFR) and PDGFR.