cSH2

cSH2 stands for the C-terminal Src Homology 2 domain, a small protein module found in signaling proteins. In humans, the best-characterized examples are the regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), which contain two SH2 domains: an N-terminal SH2 (nSH2) and a C-terminal SH2 (cSH2). The cSH2 domain is roughly 100 amino acids long and adopts the conserved SH2 fold, a central beta-sheet framework flanked by alpha helices, with a phosphotyrosine-binding pocket formed by a network of conserved residues.

The primary role of the cSH2 domain is to recognize phosphorylated tyrosine motifs on activated receptors and adaptor proteins. This binding recruits the p85-p110 PI3K heterodimer to the plasma membrane and helps orient the catalytic subunit for lipid phosphorylation, leading to production of PIP3 and activation of downstream AKT/mTOR signaling. The cSH2, together with the nSH2, also contributes to an autoinhibitory interaction that keeps p110 relatively inactive in the resting state; engagement of the SH2 domains with phosphotyrosine motifs relieves this inhibition and promotes signaling.

Specificity is determined by the surrounding amino acids in the phosphotyrosine-containing motif, guiding selective interactions with particular receptors and adapters. The cSH2 domain has been extensively studied as part of the broader SH2 domain family, which mediates many tyrosine-kinase–driven signaling events.

Clinical relevance: dysregulation of PI3K signaling, including alterations in SH2-domain–mediated interactions, is associated with cancer and metabolic diseases. Therapeutic approaches include PI3K inhibitors and strategies that target SH2-phosphotyrosine interactions to modulate pathway activity.