Phosphoinositide 3-kinase alpha-RAS protein-protein interface (PI3Kα-RAS PPI) (PI3Kα-RAS PPI)

The Phosphoinositide 3-kinase alpha (PI3Kα)-RAS protein-protein interface is a critical signaling node where the small GTPase RAS interacts with the Ras-binding domain (RBD) of the p110α catalytic subunit of PI3K (Gupta et al., 2007, Cell). This interaction is essential for the recruitment of PI3K to the plasma membrane and its subsequent activation, which triggers the AKT/mTOR signaling pathway to promote cell growth, survival, and metabolism (Rodriguez-Viciana et al., 1994, Nature). In many cancers, particularly those driven by KRAS mutations such as lung, colorectal, and pancreatic cancers, this interface is constitutively active or hyper-responsive, making it a high-priority therapeutic target (Fritsch et al., 2013, Cancer Discovery). Unlike traditional PI3K inhibitors that target the ATP-binding pocket of the kinase, inhibitors of the PI3Kα-RAS interface aim to specifically decouple PI3K signaling from oncogenic RAS. This approach potentially offers a more selective therapeutic window by sparing the basal, RAS-independent functions of PI3K in normal cells. Research into small molecules like rigosertib and peptidomimetics that disrupt this interface is ongoing, with the goal of overcoming resistance mechanisms associated with direct RAS or PI3K kinase inhibition (Athuluri-Divakar et al., 2016, Cell).

Other names

p110α-RAS interfacePI3K-RAS interactionRAS-binding domain of p110αPIK3CA-RAS interface

Disruption of the physical interaction between the RAS-binding domain (RBD) of the p110α subunit of PI3K and active RAS-GTP, thereby preventing RAS-mediated recruitment and activation of PI3K at the plasma membrane.