Activation of PI3Kα by physiological effectors and by oncogenic mutations: structural and dynamic effects

Abstract

PI3Kα, a heterodimeric lipid kinase, catalyzes the conversion of phosphoinositide-4,5-bisphosphate (PIP2) to phosphoinositide-3,4,5-trisphosphate (PIP3), a lipid that recruits to the plasma membrane proteins that regulate signaling cascades that control key cellular processes such as cell proliferation, carbohydrate metabolism, cell motility, and apoptosis. PI3Kα is composed of two subunits, p110α and p85, that are activated by binding to phosphorylated receptor tyrosine kinases (RTKs) or their substrates. The gene coding for p110α, PIK3CA, has been found to be mutated in a large number of tumors; these mutations result in increased PI3Kα kinase activity. The structure of the complex of p110α with a fragment of p85 containing the nSH2 and the iSH2 domains has provided valuable information about the mechanisms underlying the physiological activation of PI3Kα and its pathological activation by oncogenic mutations. This review discusses information derived from x-ray diffraction and theoretical calculations regarding the structural and dynamic effects of mutations in four highly mutated regions of PI3K p110α, as well as the proposed mechanisms by which these mutations increase kinase activity. During the physiological activation of PI3Kα, the phosphorylated tyrosine of RTKs binds to the nSH2 domain of p85, dislodging an inhibitory interaction between the p85 nSH2 and a loop of the helical domain of p110α. Several of the oncogenic mutations in p110α activate the enzyme by weakening this autoinhibitory interaction. These effects involve structural changes as well as changes in the dynamics of the enzyme. One of the most common p110α mutations, H1047R, activates PI3Kα by a different mechanism: it increases the interaction of the enzyme with the membrane, maximizing the access of the PI3Kα to its substrate PIP2, a membrane lipid.

Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes

“…It is required for the stabilization and localization of p110–PI3K activity to activate Akt (ref. 32). The PI3K/Akt pathway plays a wide range of roles such as proliferative and anti-apoptotic signalling, and insulin responses33.…”

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

“…They also describe a new function for PI3Ka in growth factor gene expression. PI3Ka is an oncogene frequently mutated in human cancer and has been shown to play a role in tumor progression (83). New findings that the PI3Ka isoform is also involved in PDGF-mediated prodestructive functions of RA synovial cells suggest that dual inhibition PI3Ka and PI3Kd may protect from cartilage damage by modulating the overactive prodestructive functions of synoviocytes.…”

Calmodulin and PI3K Signaling in KRAS Cancers

“…PI3Kα is regulated through its membrane binding ability and the population of effective phosphate transfer transition complexes [57–59]. These events are structurally coupled, as reflected in the K m , the PIP 2 concentration at which PI3Kα is at half of its maximal catalytic rate ( k a ).…”