Abstract
The dysregulation of phosphatidylinositol 3-kinase (PI3K) signaling plays a pivotal role in driving neoplastic transformation by promoting uncontrolled cell survival and proliferation. This oncogenic activity is primarily caused by mutations that are frequently found in PI3K genes and constitutively activate the PI3K signaling pathway. However, tumorigenesis can also arise from nonmutated PI3K proteins adopting unique active conformations, further complicating the understanding of PI3K-driven cancers. Recent structural studies have illuminated the functional divergence among highly homologous PI3K proteins, revealing how subtle structural alterations significantly impact their activity and contribute to tumorigenesis. In this review, we summarize current knowledge of Class I PI3K proteins and aim to unravel the complex mechanism underlying their oncogenic traits. These insights will not only enhance our understanding of PI3K-mediated oncogenesis but also pave the way for the design of novel PI3K-based therapies to combat cancers driven by this signaling pathway.