Sugimoto, Y., Whitman, M., Cantley, L. C. & Erikson, R. L. Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc. Natl Acad. Sci. USA 81, 2117–2121 (1984).
Article CAS PubMed PubMed Central Google Scholar
Stoyanov, B. et al. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science 269, 690–693 (1995).
Article CAS PubMed Google Scholar
Stephens, L. R., Hughes, K. T. & Irvine, R. F. Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils. Nature 351, 33–39 (1991).
Article CAS PubMed Google Scholar
Cash, J. N. et al. Cryo-electron microscopy structure and analysis of the P-Rex1-Gβγ signaling scaffold. Sci. Adv. 5, eaax8855 (2019).
Article CAS PubMed PubMed Central Google Scholar
Vanhaesebroeck, B., Perry, M. W. D., Brown, J. R., André, F. & Okkenhaug, K. PI3K inhibitors are finally coming of age. Nat. Rev. Drug Discov. 20, 741–769 (2021).
Article CAS PubMed PubMed Central Google Scholar
Deladeriere, A. et al. The regulatory subunits of PI3Kγ control distinct neutrophil responses. Sci. Signal 8, ra8 (2015).
Campa, C. C. et al. Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis. Nat. Commun. 9, 5232 (2018).
Article CAS PubMed PubMed Central Google Scholar
Chung, W. C., Zhou, X., Atfi, A. & Xu, K. PIK3CG is a potential therapeutic target in androgen receptor-indifferent metastatic prostate cancer. Am. J. Pathol. 190, 2194–2202 (2020).
Article CAS PubMed Google Scholar
Torres, C. et al. p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity. Proc. Natl Acad. Sci. USA 116, 14724–14733 (2019).
Article CAS PubMed PubMed Central Google Scholar
Stephens, L. et al. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta gamma subunits. Cell 77, 83–93 (1994).
Article CAS PubMed Google Scholar
Rathinaswamy, M. K. et al. Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation. Sci. Adv. 7, eabj4282 (2021).
Article CAS PubMed PubMed Central Google Scholar
Stephens, L. R. et al. The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 89, 105–114 (1997).
Article CAS PubMed Google Scholar
Brock, C. et al. Roles of G beta gamma in membrane recruitment and activation of p110 gamma/p101 phosphoinositide 3-kinase gamma. J. Cell Biol. 160, 89–99 (2003).
Article CAS PubMed PubMed Central Google Scholar
Vadas, O. et al. Molecular determinants of PI3Kγ-mediated activation downstream of G-protein-coupled receptors (GPCRs). Proc. Natl Acad. Sci. USA 110, 18862–18867 (2013).
Article CAS PubMed PubMed Central Google Scholar
Khalil, B. D. et al. GPCR signaling mediates tumor metastasis via PI3Kβ. Cancer Res. 76, 2944–2953 (2016).
Article CAS PubMed PubMed Central Google Scholar
Sievers, F. et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol. Syst. Biol. 7, 539 (2011).
Article PubMed PubMed Central Google Scholar
Zhang, X. et al. Structure of lipid kinase p110β/p85β elucidates an unusual SH2-domain-mediated inhibitory mechanism. Mol. Cell 41, 567–578 (2011).
Article CAS PubMed PubMed Central Google Scholar
Hart, J. R. et al. Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα. Proc. Natl Acad. Sci. USA 119, e2210769119 (2022).
Article CAS PubMed PubMed Central Google Scholar
Spencer, J. A. et al. Design and development of a macrocyclic series targeting phosphoinositide 3-kinase δ. ACS Med. Chem. Lett. 11, 1386–1391 (2020).
Article CAS PubMed PubMed Central Google Scholar
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).
Article CAS PubMed PubMed Central Google Scholar
Tesmer, J. J. Pharmacology. Hitting the hot spots of cell signaling cascades. Science 312, 377–378 (2006).
Article CAS PubMed Google Scholar
Rathinaswamy, M. K. et al. Molecular basis for differential activation of p101 and p84 complexes of PI3Kγ by Ras and GPCRs. Cell Rep. 42, 112172 (2023).
Article CAS PubMed PubMed Central Google Scholar
Gangadhara, G. et al. A class of highly selective inhibitors bind to an active state of PI3Kγ. Nat. Chem. Biol. 15, 348–357 (2019).
Article CAS PubMed Google Scholar
Rynkiewicz, N. K. et al. Gβγ is a direct regulator of endogenous p101/p110γ and p84/p110γ PI3Kγ complexes in mouse neutrophils. Sci. Signal 13, 656 (2020).
Scott, J. K. et al. Evidence that a protein–protein interaction ‘hot spot’ on heterotrimeric G protein betagamma subunits is used for recognition of a subclass of effectors. EMBO J. 20, 767–776 (2001).
Article CAS PubMed PubMed Central Google Scholar
Falzone, M. E. & MacKinnon, R. Gβγ activates PIP2 hydrolysis by recruiting and orienting PLCβ on the membrane surface. Proc. Natl Acad. Sci. USA 120, e2301121120 (2023).
Article CAS PubMed PubMed Central Google Scholar
Kurig, B. et al. Ras is an indispensable coregulator of the class IB phosphoinositide 3-kinase p87/p110gamma. Proc. Natl Acad. Sci. USA 106, 20312–20317 (2009).
Article CAS PubMed PubMed Central Google Scholar
Krugmann, S., Cooper, M. A., Williams, D. H., Hawkins, P. T. & Stephens, L. R. Mechanism of the regulation of type IB phosphoinositide 3OH-kinase byG-protein betagamma subunits. Biochem. J. 362, 725–731 (2002).
Article CAS PubMed PubMed Central Google Scholar
Pacold, M. E. et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 103, 931–943 (2000).
Article CAS PubMed Google Scholar
Miller, M. S. et al. Structural basis of nSH2 regulation and lipid binding in PI3Kα. Oncotarget 5, 5198–5208 (2014).
Article PubMed PubMed Central Google Scholar
Maier, U., Babich, A. & Nürnberg, B. Roles of non-catalytic subunits in gbetagamma-induced activation of class I phosphoinositide 3-kinase isoforms beta and gamma. J. Biol. Chem. 274, 29311–29317 (1999).
Article CAS PubMed Google Scholar
Tate, J. G. et al. COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 47, D941–D947 (2019).
Article CAS PubMed Google Scholar
Bouley, R. A. et al. A new paroxetine-based GRK2 inhibitor reduces internalization of the μ-opioid receptor. Mol. Pharmacol. 97, 392–401 (2020).
Article CAS PubMed PubMed Central Google Scholar
Chen, C. L., Paul, L. N., Mermoud, J. C., Steussy, C. N. & Stauffacher, C. V. Visualizing the enzyme mechanism of mevalonate diphosphate decarboxylase. Nat. Commun. 11, 3969 (2020).
Article CAS PubMed PubMed Central Google Scholar
Tesmer, V. M., Kawano, T., Shankaranarayanan, A., Kozasa, T. & Tesmer, J. J. Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex. Science 310, 1686–1690 (2005).
Article CAS PubMed Google Scholar
Suloway, C. et al. Automated molecular microscopy: the new Leginon system. J. Struct. Biol. 151, 41–60 (2005).
Comments (0)