Molecular basis for regulation of the class I phosphoinositide 3-kinases (PI3Ks), and their targeting in human disease

Abstract

The class I phosphoinositide 3-kinase pathway (PI3K) is a master regulator of cellular growth, and plays essential roles in controlling immune cell function, metabolism, chemotaxis and proliferation. Activation of class I PI3Ks generates the signalling lipid PIP₃ that activates multiple pro-growth signalling pathways. Class I PI3Ks can be activated by multiple plasma membrane stimuli, including G-protein coupled receptors, Ras superfamily GTPases, and receptor tyrosine kinases. The dysregulation of class I PI3Ks is critical in the progression of many human diseases, including cancers, immunodeficiencies, and developmental disorders. Highlighting this is frequent oncogenic mutations (2nd most frequently mutated gene in all human cancers) in PIK3CA encoding the p110α catalytic subunit of class IA PI3K. The class I PI3Ks are obligate heterodimers composed of a catalytic and regulatory subunit, split into two subclasses, class IA and class IB. Recent elucidation of the structures of class I PI3Ks bound to activating stimuli, with activating disease-linked mutations and bound to allosteric conformational selective inhibitors/activators, has revealed extensive insight into the molecular basis of class I PI3K regulation. This review will summarize our current molecular knowledge of class I PI3K regulation, as well as how this information is being used to generate both small molecules and biologics that can either inhibit or activate kinase activity as potential therapeutic agents and biochemical tools.