Meta-Biol

• Pathways

PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995). In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2, facilitating phosphorylation (Mandelker et al. 2009, Burke et al. 2011; reviewed in Koyasu et al, 2003; Engelman et al, 2006).