Download
59.full.pdf 1,58MB
WeightNameValue
1000 Titel
  • Different inhibition of Gβγ-stimulated class IB phosphoinositide 3-kinase (PI3K) variants by a monoclonal antibody. Specific function of p101 as a Gβγ-dependent regulator of PI3Kγ enzymatic activity
1000 Autor/in
  1. Shymanets, Aliaksei |
  2. Vadas, Oscar |
  3. Czupalla, Cornelia |
  4. LoPiccolo, Jaclyn |
  5. Brenowitz, Michael |
  6. Ghigo, Alessandra |
  7. Hirsch, Emilio |
  8. Krause, Eberhard |
  9. Wetzker, Reinhard |
  10. Williams, Roger L. |
  11. Harteneck, Christian |
  12. Nürnberg, Bernd |
1000 Erscheinungsjahr 2015
1000 LeibnizOpen
1000 Art der Datei
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2015-06-19
1000 Erschienen in
1000 Quellenangabe
  • 469(1): 59-69
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2015
1000 Lizenz
1000 Verlagsversion
  • http://doi.org/10.1042/BJ20150099 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655608/ |
1000 Ergänzendes Material
  • http://www.biochemj.org/content/469/1/59.figures-only |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Class IB phosphoinositide 3-kinases γ (PI3Kγ) are second-messenger-generating enzymes downstream of signalling cascades triggered by G-protein-coupled receptors (GPCRs). PI3Kγ variants have one catalytic p110γ subunit that can form two different heterodimers by binding to one of a pair of non-catalytic subunits, p87 or p101. Growing experimental data argue for a different regulation of p87–p110γ and p101–p110γ allowing integration into distinct signalling pathways. Pharmacological tools enabling distinct modulation of the two variants are missing. The ability of an anti-p110γ monoclonal antibody [mAb(A)p110γ] to block PI3Kγ enzymatic activity attracted us to characterize this tool in detail using purified proteins. In order to get insight into the antibody–p110γ interface, hydrogen–deuterium exchange coupled to MS (HDX-MS) measurements were performed demonstrating binding of the monoclonal antibody to the C2 domain in p110γ, which was accompanied by conformational changes in the helical domain harbouring the Gβγ-binding site. We then studied the modulation of phospholipid vesicles association of PI3Kγ by the antibody. p87–p110γ showed a significantly reduced Gβγ-mediated phospholipid recruitment as compared with p101–p110γ. Concomitantly, in the presence of mAb(A)p110γ, Gβγ did not bind to p87–p110γ. These data correlated with the ability of the antibody to block Gβγ-stimulated lipid kinase activity of p87–p110γ 30-fold more potently than p101–p110γ. Our data argue for differential regulatory functions of the non-catalytic subunits and a specific Gβγ-dependent regulation of p101 in PI3Kγ activation. In this scenario, we consider the antibody as a valuable tool to dissect the distinct roles of the two PI3Kγ variants downstream of GPCRs.
1000 Sacherschließung
lokal p101
lokal signal transduction
lokal G-protein
lokal Gβγ
lokal 3-kinase γ (PI3Kγ)
lokal p87
lokal phosphoinositide
1000 Fachgruppe
  1. Biologie |
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/creator/U2h5bWFuZXRzLCBBbGlha3NlaQ==|https://frl.publisso.de/adhoc/creator/VmFkYXMsIE9zY2Fy|https://frl.publisso.de/adhoc/creator/Q3p1cGFsbGEsIENvcm5lbGlh|https://frl.publisso.de/adhoc/creator/TG9QaWNjb2xvLCBKYWNseW4=|https://frl.publisso.de/adhoc/creator/QnJlbm93aXR6LCBNaWNoYWVs|https://frl.publisso.de/adhoc/creator/R2hpZ28sIEFsZXNzYW5kcmE=|https://frl.publisso.de/adhoc/creator/SGlyc2NoLCBFbWlsaW8=|https://frl.publisso.de/adhoc/creator/S3JhdXNlLCBFYmVyaGFyZA==|https://frl.publisso.de/adhoc/creator/V2V0emtlciwgUmVpbmhhcmQ=|https://frl.publisso.de/adhoc/creator/V2lsbGlhbXMsIFJvZ2VyIEwu|https://frl.publisso.de/adhoc/creator/SGFydGVuZWNrLCBDaHJpc3RpYW4=|https://frl.publisso.de/adhoc/creator/TsO8cm5iZXJnLCBCZXJuZA==
1000 Label
1000 Förderer
  1. Deutsche Forschungsgemeinschaft |
  2. Telethon |
  3. Swiss National Science Foundation fellowship |
  4. European Commission fellowship |
  5. Medical Research Council |
1000 Fördernummer
  1. IRTG 1302; RTG 1715
  2. GGP14106
  3. PA00P3_134202
  4. FP7-PEOPLE-2010-IEF; N°275880
  5. U10518430
1000 Förderprogramm
  1. -
  2. -
  3. -
  4. FP7
  5. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft |
    1000 Förderprogramm -
    1000 Fördernummer IRTG 1302; RTG 1715
  2. 1000 joinedFunding-child
    1000 Förderer Telethon |
    1000 Förderprogramm -
    1000 Fördernummer GGP14106
  3. 1000 joinedFunding-child
    1000 Förderer Swiss National Science Foundation fellowship |
    1000 Förderprogramm -
    1000 Fördernummer PA00P3_134202
  4. 1000 joinedFunding-child
    1000 Förderer European Commission fellowship |
    1000 Förderprogramm FP7
    1000 Fördernummer FP7-PEOPLE-2010-IEF; N°275880
  5. 1000 joinedFunding-child
    1000 Förderer Medical Research Council |
    1000 Förderprogramm -
    1000 Fördernummer U10518430
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6405093.rdf
1000 Erstellt am 2017-10-20T14:50:55.659+0200
1000 Erstellt von 25
1000 beschreibt frl:6405093
1000 Bearbeitet von 218
1000 Zuletzt bearbeitet Thu Jan 30 16:00:34 CET 2020
1000 Objekt bearb. Tue Jul 31 11:50:37 CEST 2018
1000 Vgl. frl:6405093
1000 Oai Id
  1. oai:frl.publisso.de:frl:6405093 |
1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
1000 Gegenstand von

View source