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Dosage‐dependent regulation of cell proliferation and adhesion through dual β 2 ‐adrenergic receptor/cAMP signals
Author(s) -
Bruzzone Ariana,
Saulière Aude,
Finana Frédéric,
Sénard JeanMichel,
Lüthy Isabel,
Galés Céline
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-239285
Subject(s) - agonist , signal transduction , phosphorylation , receptor , microbiology and biotechnology , adhesion , population , chemistry , cell adhesion , cell growth , endocrinology , medicine , biology , biochemistry , environmental health , organic chemistry
The role of β‐adrenergic receptors (β‐ARs) remains controversial in normal and tumor breast. Herein we explore the cAMP signaling involved in β ‐AR‐dependent control of proliferation and adhesion of nontumor human breast cell line MCF‐10A. Low concentrations of a β‐agonist, isoproterenol (ISO), promote cell adhesion (87.5% cells remaining adherent to the plastic dishes following specific detachment vs. 35.0% in control, P <0.001), while increasing concentrations further engages an additional 36% inhibition of Erk1/2 phosphorylation (p‐Erk1/2)‐dependent cell proliferation ( P <0.01). Isoproterenol dose response on cell adhesion was fitted to a 2‐site curve (EC 50 (1): 16.5±11.5 fM, EC 50 (2): 4.08 ±3.09 nM), while ISO significantly inhibited p‐Erk1/2 according to a 1‐site model (EC 50 : 0.25 ±0.13 nM). Using β‐AR‐selective agonist/antagonists and cAMP analogs/inhibitors, we identified a dosage‐dependent signaling in which low ISO concentrations target a β 2 ‐AR population localized in raft microdomains and stimulate a G s /cAMP/Epac/ adhesion‐signaling module, while higher concentrations engage a concomitant activation of another β 2 ‐AR population outside rafts and inhibit the proliferation by a G s /cAMP/PKA‐dependent signaling module. Our data provide a new molecular basis for the dose‐dependent switch of β‐AR signaling. This study also sheds light on a new cAMP pathway core mechanism with a single receptor triggering dual cAMP signaling controlled by PKA or Epac but with different cellular outputs.—Bruzzone, A., Saulière, A., Finana, F., Sénard, J.‐M., Lüthy, I., Galés, C. Dosage‐dependent regulation of cell proliferation and adhesion through dual β 2 ‐adrenergic receptor/cAMP signals. FASEB J. 28, 1342–1354 (2014). www.fasebj.org