SH2containing

SH2-containing proteins are proteins that harbor Src Homology 2 (SH2) domains, small modular phosphotyrosine-binding modules that play a central role in cellular signaling. The SH2 domain is typically about 100 amino acids in length and folds into a compact structure consisting of a central beta-sheet flanked by alpha-helices. It recognizes phosphotyrosine-containing motifs on target proteins, with binding specificity determined by residues surrounding the phosphotyrosine and, in some cases, by adjacent amino acids.

In signaling pathways, SH2 domains enable proteins to bind to tyrosine-phosphorylated receptors or other signaling proteins, facilitating the assembly of signaling complexes, recruitment of downstream effectors, and propagation of signals. This modular binding enables SH2-containing proteins to function as adaptors, regulators, or enzymes, often in combination with other domains such as SH3, PH, or kinase domains.

Prominent examples include Grb2, Crk, and Nck, which act as adaptors linking receptor tyrosine kinases to Ras-MAPK pathways; SHP-1 and SHP-2, protein tyrosine phosphatases containing SH2 domains; and regulatory subunits of PI3K such as p85. The Src family kinase Src itself contains an SH2 domain that participates in intramolecular and intermolecular interactions.

Dysregulation or mutation of SH2-containing proteins can contribute to disease. For instance, mutations in SH2D1A cause X-linked lymphoproliferative disease, and PTPN11 mutations in SHP-2 are associated with Noonan syndrome and certain leukemias. SH2-containing proteins are evolutionarily conserved and fundamental to transducing signals from activated kinases to diverse cellular responses.