Defining How Oncogenic and Developmental Mutations of PIK3R1 Alter the Regulation of Class IA Phosphoinositide 3-Kinases

Gillian L Dornan; Jordan T B Stariha; Manoj K Rathinaswamy; Cameron J Powell; Martin J Boulanger; John E Burke

doi:10.1016/j.str.2019.11.013

Defining How Oncogenic and Developmental Mutations of PIK3R1 Alter the Regulation of Class IA Phosphoinositide 3-Kinases

Structure. 2020 Feb 4;28(2):145-156.e5. doi: 10.1016/j.str.2019.11.013. Epub 2019 Dec 9.

Authors

Gillian L Dornan¹, Jordan T B Stariha¹, Manoj K Rathinaswamy¹, Cameron J Powell¹, Martin J Boulanger¹, John E Burke²

Affiliations

¹ Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8W 2Y2, Canada.
² Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8W 2Y2, Canada. Electronic address: [email protected].

PMID: 31831213
DOI: 10.1016/j.str.2019.11.013

Abstract

The class I phosphoinositide 3-kinases (PI3Ks) are key signaling enzymes composed of a heterodimer of a p110 catalytic subunit and a p85 regulatory subunit, with PI3K mutations being causative of multiple human diseases including cancer, primary immunodeficiencies, and developmental disorders. Mutations in the p85α regulatory subunit encoded by PIK3R1 can both activate PI3K through oncogenic truncations in the iSH2 domain, or inhibit PI3K through developmental disorder mutations in the cSH2 domain. Using a combined biochemical and hydrogen deuterium exchange mass spectrometry approach we have defined the molecular basis for how these mutations alter the activity of p110α/p110δ catalytic subunits. We find that the oncogenic Q572^∗ truncation of PIK3R1 disrupts all p85-inhibitory inputs, with p110α being hyper-activated compared with p110δ. In addition, we find that the R649W mutation in the cSH2 of PIK3R1 decreases sensitivity to activation by receptor tyrosine kinases. This work reveals unique insight into isoform-specific regulation of p110s by p85α.

Keywords: HDX-MS; PI3K; PI3K-Akt; PIK3CA; PIK3R1; hydrogen exchange; p110; p85; phosphoinositide 3-kinase; phosphoinositides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Catalytic Domain
Class I Phosphatidylinositol 3-Kinases / chemistry
Class I Phosphatidylinositol 3-Kinases / metabolism*
Class Ia Phosphatidylinositol 3-Kinase / chemistry
Class Ia Phosphatidylinositol 3-Kinase / genetics*
Enzyme Activation
Humans
Hydrogen Deuterium Exchange-Mass Spectrometry
Models, Molecular
Mutation*
Protein Conformation
Protein Domains

Substances

PIK3R1 protein, human
Class I Phosphatidylinositol 3-Kinases
Class Ia Phosphatidylinositol 3-Kinase
PIK3CA protein, human
PIK3CD protein, human