Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells

Daniel M. Houslay, Karen E. Anderson, Tamara Chessa, Suhasini Kulkarni, Ralph Fritsch, Julian Downward, Jonathan M. Backer, Len R. Stephens, Phillip T. Hawkins

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Class I phosphoinositide 3-kinases (PI3Ks) catalyze production of the lipid messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), which plays a central role in a complex signaling network regulating cell growth, survival, and movement. This network is overactivated in cancer and inflammation, and there is interest in determining the PI3K catalytic subunit (p110α, p110β, p110γ, or p110δ) that should be targeted in different therapeutic contexts. Previous studies have defined unique regulatory inputs for p110β, including direct interaction with Gβγ subunits, Rac, and Rab5. We generated mice with knock-in mutations of p110β that selectively blocked the interaction with Gβgγ and investigated its contribution to the PI3K isoform dependency of receptor tyrosine kinase (RTK) and G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) responses in primary macrophages and neutrophils. We discovered a unique role for p110β in supporting synergistic PIP3 formation in response to the coactivation of macrophages by macrophage colony-stimulating factor (M-CSF) and the complement protein C5a. In contrast, we found partially redundant roles for p110α, p110β, and p110δ downstream of M-CSF alone and a nonredundant role for p110γ downstream of C5a alone. This role for p110β completely depended on direct interaction with Gβγ, suggesting that p110β transduces GPCR signals in the context of coincident activation by an RTK. The p110β-Gβγ interaction was also required for neutrophils to generate reactive oxygen species in response to the Fcγ receptor-dependent recognition of immune complexes and for their β2 integrin-mediated adhesion to fibrinogen or poly-RGD+, directly implicating heterotrimeric G proteins in these two responses.

Original languageEnglish (US)
Article numberra82
JournalScience Signaling
Volume9
Issue number441
DOIs
StatePublished - Aug 16 2016

Fingerprint

1-Phosphatidylinositol 4-Kinase
Receptor Protein-Tyrosine Kinases
Myeloid Cells
Phosphatidylinositols
Macrophage Colony-Stimulating Factor
Phosphotransferases
Guanine Nucleotides
Macrophages
Carrier Proteins
Neutrophils
Complement C5a
Heterotrimeric GTP-Binding Proteins
Fc Receptors
Cell growth
Antigen-Antibody Complex
Integrins
Fibrinogen
Cell Movement
Reactive Oxygen Species
Catalytic Domain

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Houslay, D. M., Anderson, K. E., Chessa, T., Kulkarni, S., Fritsch, R., Downward, J., ... Hawkins, P. T. (2016). Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells. Science Signaling, 9(441), [ra82]. https://doi.org/10.1126/scisignal.aae0453

Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells. / Houslay, Daniel M.; Anderson, Karen E.; Chessa, Tamara; Kulkarni, Suhasini; Fritsch, Ralph; Downward, Julian; Backer, Jonathan M.; Stephens, Len R.; Hawkins, Phillip T.

In: Science Signaling, Vol. 9, No. 441, ra82, 16.08.2016.

Research output: Contribution to journalArticle

Houslay, DM, Anderson, KE, Chessa, T, Kulkarni, S, Fritsch, R, Downward, J, Backer, JM, Stephens, LR & Hawkins, PT 2016, 'Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells', Science Signaling, vol. 9, no. 441, ra82. https://doi.org/10.1126/scisignal.aae0453
Houslay, Daniel M. ; Anderson, Karen E. ; Chessa, Tamara ; Kulkarni, Suhasini ; Fritsch, Ralph ; Downward, Julian ; Backer, Jonathan M. ; Stephens, Len R. ; Hawkins, Phillip T. / Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells. In: Science Signaling. 2016 ; Vol. 9, No. 441.
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