Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 9 June 2009
Vol. 2, Issue 74, p. ra27
[DOI: 10.1126/scisignal.2000259]

RESEARCH ARTICLES

PI3K{gamma} Adaptor Subunits Define Coupling to Degranulation and Cell Motility by Distinct PtdIns(3,4,5)P3 Pools in Mast Cells

Thomas Bohnacker1, Romina Marone1*, Emilie Collmann1*, Ronan Calvez1{dagger}, Emilio Hirsch2, and Matthias P. Wymann1{ddagger}

1 Institute of Biochemistry and Genetics, Department of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland.
2 Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Via Nizza 52, I-10126 Turin, Italy.

* These authors contributed equally to this work.

{dagger} Present address: Marie Curie Excellence Team, INSERM U563, CHU Purpan, BP 3028, 31024 Toulouse Cedex 3, France.

Abstract: Phosphoinositide 3-kinase {gamma} (PI3K{gamma}) plays a major role in chronic inflammation and allergy. It is a heterodimer of a catalytic p110{gamma} subunit and an adaptor protein, either p101 or the p101 homolog p84 (p87PIKAP). It is unclear whether both PI3K{gamma} complexes specifically modulate responses such as chemotaxis and degranulation. In mast cells, the p84:p110{gamma} complex synergizes with immunoglobulin E (IgE)– and antigen-clustered Fc{varepsilon}RI receptor signaling and is required to achieve maximal degranulation. During this process, PI3K{gamma} is activated by ligands of heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs), in particular adenosine receptors, through autocrine and paracrine pathways. Here, we show that p110{gamma} needs p84 to relay signals from GPCRs to formation of phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], phosphorylation of Akt, migration of cells, and synergistic adenosine-enforced degranulation. Furthermore, the absence of adaptor subunits could not be compensated for by increased p110{gamma} abundance. Differentiated, p110{gamma} null cells also lost adaptor proteins. Complementation of p110{gamma} null mast cells with p101 and p110{gamma} restored the activation of Akt and cell migration, but failed to support degranulation. Lack of degranulation was attributed to a change in the spatiotemporal localization of PI3K{gamma}-derived PtdIns(3,4,5)P3; although both p84:p110{gamma} and p101:p110{gamma} complexes initially deposited PtdIns(3,4,5)P3 at the plasma membrane, p101:p110{gamma}–derived PtdIns(3,4,5)P3 was rapidly endocytosed to motile, microtubule-associated vesicles. In addition, p84:p110{gamma}, but not p101:p110{gamma} signaling was sensitive to disruption of lipid rafts. Our results demonstrate a nonredundant function for the p101 and p84 PI3K{gamma} adaptor proteins and show that distinct pools of PtdIns(3,4,5)P3 at the plasma membrane can elicit specific cell responses.

{ddagger} To whom correspondence should be addressed. E-mail: Matthias.Wymann{at}UniBas.ch

Citation: T. Bohnacker, R. Marone, E. Collmann, R. Calvez, E. Hirsch, M. P. Wymann, PI3K{gamma} Adaptor Subunits Define Coupling to Degranulation and Cell Motility by Distinct PtdIns(3,4,5)P3 Pools in Mast Cells. Sci. Signal. 2, ra27 (2009).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
p87 and p101 Subunits Are Distinct Regulators Determining Class IB Phosphoinositide 3-Kinase (PI3K) Specificity.
A. Shymanets, Prajwal, K. Bucher, S. Beer-Hammer, C. Harteneck, and B. Nurnberg (2013)
J. Biol. Chem. 288, 31059-31068
   Abstract »    Full Text »    PDF »
Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation.
T. Balla (2013)
Physiol Rev 93, 1019-1137
   Abstract »    Full Text »    PDF »
Inhibition of PI3K Signaling Spurs New Therapeutic Opportunities in Inflammatory/Autoimmune Diseases and Hematological Malignancies.
J. G. Foster, M. D. Blunt, E. Carter, and S. G. Ward (2012)
Pharmacol. Rev. 64, 1027-1054
   Abstract »    Full Text »    PDF »
Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane.
N. Schmidt, S. Basu, S. Sladecek, S. Gatti, J. van Haren, S. Treves, J. Pielage, N. Galjart, and H. R. Brenner (2012)
J. Cell Biol. 198, 421-437
   Abstract »    Full Text »    PDF »
Involvement of Phosphoinositide 3-Kinase and PTEN Protein in Mechanism of Activation of TRPC6 Protein in Vascular Smooth Muscle Cells.
M. Monet, N. Francoeur, and G. Boulay (2012)
J. Biol. Chem. 287, 17672-17681
   Abstract »    Full Text »    PDF »
Phosphatidylinositol 3-Kinase Signaling in Thymocytes: The Need for Stringent Control.
E. Fayard, G. Moncayo, B. A. Hemmings, and G. A. Hollander (2010)
Science Signaling 3, re5
   Abstract »    Full Text »    PDF »
The catalytic PI3K isoforms p110{gamma} and p110{delta} contribute to B cell development and maintenance, transformation, and proliferation.
S. Beer-Hammer, E. Zebedin, M. von Holleben, J. Alferink, B. Reis, P. Dresing, D. Degrandi, S. Scheu, E. Hirsch, V. Sexl, et al. (2010)
J. Leukoc. Biol. 87, 1083-1095
   Abstract »    Full Text »    PDF »
Phosphatidylinositol 3-kinase isoforms as targets in respiratory disease.
J. A. Marwick, Kian Fan Chung, and I. M. Adcock (2010)
Therapeutic Advances in Respiratory Disease 4, 19-34
   Abstract »    PDF »
Ras is an indispensable coregulator of the class IB phosphoinositide 3-kinase p87/p110{gamma}.
B. Kurig, A. Shymanets, T. Bohnacker, Prajwal, C. Brock, M. R. Ahmadian, M. Schaefer, A. Gohla, C. Harteneck, M. P. Wymann, et al. (2009)
PNAS 106, 20312-20317
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 09 June 2009.
M. P. Wymann and A. M. VanHook (2009)
Science Signaling 2, pc10
   Abstract »    Full Text »
Finding Partners for PI3K{gamma}: When 84 Is Better Than 101.
T. Balla (2009)
Science Signaling 2, pe35
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882