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      Function, Regulation and Biological Roles of PI3Kγ Variants

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          Abstract

          Phosphatidylinositide 3-kinase (PI3K) γ is the only class IB PI3K member playing significant roles in the G-protein-dependent regulation of cell signaling in health and disease. Originally found in the immune system, increasing evidence suggest a wide array of functions in the whole organism. PI3Kγ occur as two different heterodimeric variants: PI3Kγ (p87) and PI3Kγ (p101), which share the same p110γ catalytic subunit but differ in their associated non-catalytic subunit. Here we concentrate on specific PI3Kγ features including its regulation and biological functions. In particular, the roles of its non-catalytic subunits serving as the main regulators determining specificity of class IB PI3Kγ enzymes are highlighted.

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          Phosphatidylinositol-3-OH kinase as a direct target of Ras.

          P. RODRIGUEZ-VICIANA, P. Warne, R Dhand … (1994)
          Ras (p21ras) interacts directly with the catalytic subunit of phosphatidylinositol-3-OH kinase in a GTP-dependent manner through the Ras effector site. In vivo, dominant negative Ras mutant N17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in PC12 cells, and transfection of Ras, but not Raf, into COS cells results in a large elevation in the level of these lipids. Therefore Ras can probably regulate phosphatidylinositol-3-OH kinase, providing a point of divergence in signalling pathways downstream of Ras.
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            Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine.

            E. Walker, M Pacold, O Perisic … (2000)
            The specific phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY294002 have been invaluable tools for elucidating the roles of these enzymes in signal transduction pathways. The X-ray crystallographic structures of PI3Kgamma bound to these lipid kinase inhibitors and to the broad-spectrum protein kinase inhibitors quercetin, myricetin, and staurosporine reveal how these compounds fit into the ATP binding pocket. With a nanomolar IC50, wortmannin most closely fits and fills the active site and induces a conformational change in the catalytic domain. Surprisingly, LY294002 and the lead compound on which it was designed, quercetin, as well as the closely related flavonoid myricetin bind PI3K in remarkably different orientations that are related to each other by 180 degrees rotations. Staurosporine/PI3K interactions are reminiscent of low-affinity protein kinase/staurosporine complexes. These results provide a rich basis for development of isoform-specific PI3K inhibitors with therapeutic potential.
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              Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration.

              T. Sasaki, J Irie-Sasaki, R. G. Jones … (2000)
              Phosphoinositide 3-kinases (PI3Ks) regulate fundamental cellular responses such as proliferation, apoptosis, cell motility, and adhesion. Viable gene-targeted mice lacking the p110 catalytic subunit of PI3Kgamma were generated. We show that PI3Kgamma controls thymocyte survival and activation of mature T cells but has no role in the development or function of B cells. PI3Kgamma-deficient neutrophils exhibited severe defects in migration and respiratory burst in response to heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPCR) agonists and chemotactic agents. PI3Kgamma links GPCR stimulation to the formation of phosphatidylinositol 3,4,5-triphosphate and the activation of protein kinase B, ribosomal protein S6 kinase, and extracellular signal-regulated kinases 1 and 2. Thus, PI3Kgamma regulates thymocyte development, T cell activation, neutrophil migration, and the oxidative burst.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biomolecules
                Journal ID (iso-abbrev): Biomolecules
                Journal ID (publisher-id): biomolecules
                Title: Biomolecules
                Publisher: MDPI
                ISSN (Electronic): 2218-273X
                Publication date (Electronic): 30 August 2019
                Publication date Collection: September 2019
                Volume: 9
                Issue: 9
                Electronic Location Identifier: 427
                Affiliations
                [1 ]Department of Pharmacology & Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Wilhelmstrasse 56, 72074 Tübingen, Germany
                [2 ]Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Wilhelmstrasse 56, 72074 Tübingen, Germany
                Author notes
                [* ]Correspondence: bernd.nuernberg@ 123456uni-tuebingen.de ; Tel.: +49-(0)7071-29-74590
                Author information
                https://orcid.org/0000-0002-5995-6555
                Article
                Publisher ID: biomolecules-09-00427
                DOI: 10.3390/biom9090427
                PMC ID: 6770443
                PubMed ID: 31480354
                SO-VID: e240fd4c-638f-47d2-895a-fdf37f7dc2bc
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 23 July 2019
                Date accepted : 15 August 2019
                Categories
                Subject: Review

                Keywords: pi3k (phosphatidylinositide 3-kinase),class i pi3-kinases,p110γ,p87 (p84),g-proteins,gβγ,ras
                Data availability:
                Keywords: pi3k (phosphatidylinositide 3-kinase), class i pi3-kinases, p110γ, p87 (p84), g-proteins, gβγ, ras

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