GRB2

Grb2, or growth factor receptor-bound protein 2, is a widely expressed adaptor protein that links activated receptor tyrosine kinases to downstream signaling pathways. It is encoded by the GRB2 gene and is composed of an SH2 domain flanked by two SH3 domains, arranged to allow simultaneous binding to phosphotyrosine motifs and proline-rich regions. This modular architecture enables Grb2 to assemble signaling complexes at the plasma membrane.

The primary function of Grb2 is to connect receptor activation with the Ras–MAPK signaling cascade. Upon receptor stimulation, the SH2 domain binds to phosphotyrosine-containing motifs on the activated receptor or on adaptor proteins, and the SH3 domains recruit proline-rich partners such as SOS1 and SOS2, which are guanine nucleotide exchange factors for Ras. Recruitment of SOS to the membrane activates Ras, triggering the Raf–MEK–ERK cascade that governs cell proliferation, differentiation, and survival. Grb2 can participate in additional signaling modules through interactions with other adapters and effectors, contributing to the integration of signals from multiple receptors.

Key interaction partners include SOS1/2, SHC family proteins, Gab1/2, and various proline-rich proteins. Through these networks, Grb2 influences diverse cellular processes and cross-talk with other pathways, including PI3K signaling in some contexts.

Clinically, Grb2 is essential for normal development, and genetic disruption can lead to developmental defects in model organisms. Dysregulation or overexpression of Grb2 has been observed in certain cancers, making its protein–protein interactions a focus of therapeutic research, including approaches aimed at inhibiting its SH2 or SH3 domain–mediated binding.