Molecular mechanism of activation of class IA phosphoinositide 3-kinases (PI3Ks) by membrane-localized HRas.

The Journal of Biological Chemistry
Braden D SiempelkampJohn E Burke

Abstract

Class IA PI3Ks are involved in the generation of the key lipid signaling molecule phosphatidylinositol 3,4,5-trisphosphate (PIP3), and inappropriate activation of this pathway is implicated in a multitude of human diseases, including cancer, inflammation, and primary immunodeficiencies. Class IA PI3Ks are activated downstream of the Ras superfamily of GTPases, and Ras-PI3K interaction plays a key role in promoting tumor formation and maintenance in Ras-driven tumors. Investigating the detailed molecular events in the Ras-PI3K interaction has been challenging because it occurs on a membrane surface. Here, using maleimide-functionalized lipid vesicles, we successfully generated membrane-resident HRas and evaluated its effect on PI3K signaling in lipid kinase assays and through analysis with hydrogen-deuterium exchange MS. We screened all class IA PI3K isoforms and found that HRas activates both p110α and p110δ isoforms but does not activate p110β. The p110α and p110δ activation by Ras was synergistic with activation by a soluble phosphopeptide derived from receptor tyrosine kinases. Hydrogen-deuterium exchange MS revealed that membrane-resident HRas, but not soluble HRas, enhances conformational changes associated with membrane b...Continue Reading

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Citations

Jan 13, 2018·Journal of Lipid Research·Michael J Pulkoski-GrossLina M Obeid
Jan 30, 2019·The Journal of Biological Chemistry·John E Burke
Aug 5, 2017·Expert Opinion on Drug Discovery·Glenn R MassonJohn E Burke
Apr 11, 2018·Proceedings of the National Academy of Sciences of the United States of America·Iva LučićThomas A Leonard
Apr 22, 2018·Biochemical Society Transactions·Claudia Hinze, Emmanuel Boucrot
Dec 24, 2017·Cancer Research·Ruth NussinovHyunbum Jang
Apr 4, 2020·Molecular Cancer Therapeutics·Lihua ShuZhuo G Chen
Jan 3, 2021·Molecular Biology Reports·Angelo GismondiAntonella Canini
Jan 3, 2021·The FEBS Journal·Philipp Alexander KochVolker Haucke
Oct 14, 2020·Cancer Research·Mingzhen ZhangRuth Nussinov
Oct 16, 2019·Advances in Biological Regulation·Manoj K Rathinaswamy, John E Burke
Feb 5, 2021·Journal of Molecular Biology·Nicholas G MartinezSharon L Campbell
Jan 11, 2018·Journal of Chemical Information and Modeling·Chimno I NnadiNir London
Nov 9, 2017·Biophysical Journal·Mingzhen ZhangRuth Nussinov

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