2025年1月9日 · The RAS-driven activation of phosphatidylinositol 3-kinases (PI3K) amplifies the PI3K-AKT-mTOR signaling pathway, a key driver of oncogenic transformation 1,2,3,4.

2021年8月9日 · PI3K 具有 5 个结构域：N-端 ABD 结构域 (P85 结合域)、RBD 结构域 (Ras 结合域)、C2 结构域、螺旋型结构域、C 端结构域。 当配体与膜受体结合后受体发生磷酸化，这些磷酸化位点能够识别和结合 p85 调节亚单位 SH 2 结构域，并招募 p110，进而催化膜内表面的 PIP2 生成 PI3P, PI3P 作为第二信使，进一步激活 AKT 和 PDK1。 AKT 又称 PKB (protein kinase B)，是 PI3K 重要的下游分子，包括 3 种形式： AKT1、AKT2 和 AKT3。

2024年12月22日 · Active GTP-Ras binds PI3K with high affinity, thereby stimulating PIP 3 production. We hypothesize the affinity of this binding interaction could be significantly increased or decreased by Ras mutations at PI3K contact positions, with clinical implications since some Ras mutations at PI3K contact positions are disease-linked.

Ras recruitment can shift the PI3Kα ensemble toward a population where the kinase domain surface and the active site position and orientation favor PIP 2 insertion. This work helps elucidate Ras-mediated PI3K activation and explores the structural basis for Ras–PI3Kα drug discovery.

Evidence emerging in recent years suggests that both oncogenic Ras signaling in tumor cells and non-oncogenic Ras signaling in stromal cells play an essential role in cancer. PI3K is one of the main Ras effectors, regulating important cellular processes such as cell viability or resistance to therapy or angiogenesis upon oncogenic Ras activation.

PI3K has proven to be necessary for RAS-induced transformation in vitro, and more importantly, mice with mutations in the PI3K catalytic subunit p110α that block its ability to interact with RAS are highly resistant to endogenous oncogenic KRAS-induced lung tumorigenesis and HRAS-induced skin carcinogenesis.

RAS signaling through PI3K is necessary for normal lymphatic vasculature development and for RAS-induced transformation in vitro and in vivo, especially in lung cancer, where it is essential for tumor initiation and necessary for tumor maintenance.

2018年6月1日 · In this review, we summarize our current knowledge about how RAS regulates type I phosphatidylinositol 3-kinase (PI3K), one of the main RAS effectors. RAS signaling through PI3K is necessary for normal lymphatic vasculature development and for RAS-induced transformation in vitro and in vivo, especially in lung cancer, where it is essential for ...

2021年4月16日 · Phosphatidylinositol-3-kinases (PI3Ks) are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate to generate a key lipid second messenger, phosphatidylinositol 3,4,5-bisphosphate. PI3Kα and PI3Kγ require activation by RAS proteins to stimulate signaling pathways that control cellular growth, differentiation, motility and survival.

2025年1月9日 · Mutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kα and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, although the …