PI3K binds to EGF:EGFR:GRB2:GAB1

The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1(Rodrigues et al. 2000, Onishi-Haraikawa et al. 2001). 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 (Mandelker et al. 2009, Burke et al. 2011).

Src同源域2（SH2）结构域的磷脂酰肌醇3激酶（PIK3）调控亚基（PIK3R1，即PI3Kp85）以非磷酸化依赖的方式与GAB1结合。GAB1作为一种停靠蛋白，能够招募多种下游信号蛋白。PIK3R1能够与GAB1或磷酸化后的GAB1(Rodrigues等，2000年，Onishi-Haraikawa等，2001年)结合。在未受刺激的细胞中，PI3K类IA以p85调控亚基（由PIK3R1、PIK3R2或PIK3R3编码）和p110催化亚基（由PIK3CA、PIK3CB或PIK3CD编码）组成的非活性异源二聚体的形式存在。p85调控亚基的iSH2结构域与p110催化亚基的ABD和C2结构域的结合既稳定了p110，又抑制了其催化活性。当p85的SH2结构域与激活的RTK或其适配蛋白上的磷酸化酪氨酸结合时，这种抑制得以解除。与膜结合受体的结合将激活的PI3K置于其膜定位底物PIP2的邻近位置（Mandelker等，2009年，Burke等，2011年）。