Ras-binding domain of Phosphoinositide 3-kinase (PI3K) isoforms (PI3K RBD)

The Ras-binding domain (RBD) of Phosphoinositide 3-kinase (PI3K) isoforms is a specialized structural region located within the catalytic p110 subunits (α, β, γ, and δ) of Class I PI3Ks [1, 2]. This domain serves as a critical regulatory interface that facilitates the direct interaction between PI3K and activated, GTP-bound Ras GTPases, such as KRAS, HRAS, and NRAS [2, 4]. This interaction is essential for the recruitment of PI3K to the plasma membrane, where it converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby initiating downstream signaling through the AKT/mTOR pathway [1, 4]. In many human cancers, particularly those with oncogenic Ras mutations, the Ras-PI3K interaction is constitutively active, driving uncontrolled cell proliferation, survival, and metabolic reprogramming [3, 4]. Consequently, the PI3K RBD has emerged as a significant therapeutic target for the development of protein-protein interaction (PPI) inhibitors [3]. These inhibitors aim to selectively disrupt the coupling of PI3K to oncogenic Ras, potentially offering a more targeted therapeutic window with fewer off-target effects compared to traditional ATP-competitive PI3K inhibitors [3, 4].

Other names

PI3K Ras-binding domainp110 Ras-binding domainPhosphoinositide 3-kinase Ras-binding domainRas-binding domain of p110

Disruption of the protein-protein interaction (PPI) between activated Ras GTPases and the PI3K catalytic subunit by binding to the Ras-binding domain (RBD), which prevents the membrane recruitment and subsequent activation of the PI3K/AKT signaling pathway [2, 3].