SH2SH3containing

SH2SH3containing refers to a class of proteins that possess both Src homology 2 (SH2) and Src homology 3 (SH3) domains within their primary structure. These modular domains enable the proteins to serve as key adapters or scaffold molecules in intracellular signaling pathways, linking receptor activation to downstream effectors.

The SH2 domain is a small beta-sandwich module that binds phosphotyrosine residues on activated receptors or cytoplasmic proteins. The SH3 domain typically interacts with proline-rich motifs (PxxP) in partner proteins, mediating protein‑protein interactions that are independent of phosphorylation. The combination of these two domains within a single polypeptide allows SH2SH3containing proteins to coordinate multiple signaling events, acting as bridges between activated receptors and downstream signaling complexes.

Several important signaling proteins belong to this category, including Sos1 and Sos2, which act as guanine nucleotide exchange factors for Ras; Grb2, which links receptor tyrosine kinases to SOS; and Csk, a kinase that negatively regulates Src family kinases. Other members such as Ras-GRF2, Nck1/2, and ShcA also contain both domains and are involved in diverse cellular processes ranging from cell growth to cytoskeletal reorganization.

In the context of cellular signaling, SH2SH3containing proteins typically function as adaptor or scaffolding proteins rather than catalytic enzymes. They contribute to the assembly of multi-protein signalosomes, regulate the activity of kinases and GTPases, and modulate the spatial and temporal aspects of signal propagation. Their activity is tightly regulated by phosphorylation, interaction with lipids, and subcellular localization.

Aberrant expression or mutation of SH2SH3containing proteins has been implicated in multiple diseases, most notably cancers and immune disorders. For example, gain‑of‑function mutations in Grb2 and Sos lead to hyperactive Ras signaling, while altered ShcA signaling contributes to tumor progression. Consequently, these proteins are active targets in drug discovery efforts, with research focusing on disrupting specific domain interactions to modulate pathological signaling pathways.