Receptor-specific regulation of ERK1/2 activation by members of the “free fatty acid receptor” family
S Seljeset, S Siehler - Journal of Receptors and Signal …, 2012 - Taylor & Francis
S Seljeset, S Siehler
Journal of Receptors and Signal Transduction, 2012•Taylor & FrancisContext: The “free fatty acid receptors”(FFARs) GPR40, GPR41, and GPR43 regulate
various physiological homeostases, and are all linked to activation of extracellular signal-
regulated kinases (ERK) 1/2. Objective: Investigation of coupling of FFARs to two other
mitogen-activated protein kinases (MAPKs) sometimes regulated by G protein-coupled
receptors (GPCRs), c-Jun N-terminal kinase (JNK) and p38MAPK, and characterization of
signaling proteins involved in the regulation of FFAR-mediated ERK1/2 activation. Methods …
various physiological homeostases, and are all linked to activation of extracellular signal-
regulated kinases (ERK) 1/2. Objective: Investigation of coupling of FFARs to two other
mitogen-activated protein kinases (MAPKs) sometimes regulated by G protein-coupled
receptors (GPCRs), c-Jun N-terminal kinase (JNK) and p38MAPK, and characterization of
signaling proteins involved in the regulation of FFAR-mediated ERK1/2 activation. Methods …
Context: The “free fatty acid receptors” (FFARs) GPR40, GPR41, and GPR43 regulate various physiological homeostases, and are all linked to activation of extracellular signal-regulated kinases (ERK)1/2.
Objective: Investigation of coupling of FFARs to two other mitogen-activated protein kinases (MAPKs) sometimes regulated by G protein-coupled receptors (GPCRs), c-Jun N-terminal kinase (JNK) and p38MAPK, and characterization of signaling proteins involved in the regulation of FFAR-mediated ERK1/2 activation.
Methods: FFARs were recombinantly expressed, cells challenged with the respective agonist, and MAPK activation quantitatively determined using an AlphaScreen SureFire assay. Inhibitors for signaling proteins were utilized to characterize ERK1/2 pathways.
Results: Propionate-stimulated GPR41 strongly coupled to ERK1/2 activation, while the coupling of linoleic acid-activated GPR40 and acetate-activated GPR43 was weaker. JNK and p38MAPK were weakly activated by FFARs. All three receptors activated ERK1/2 fully or partially via Gi/o and Rac. PI3K was relevant for GPR40- and GPR41-mediated ERK1/2 activation, and Src was essential for GPR40- and GPR43-induced activation. Raf-1 was not involved in the GPR43-triggered activation.
Conclusion: The results demonstrate a novel role of Rac in GPCR-mediated ERK1/2 signaling, and that GPCRs belonging to the same family can regulate ERK1/2 activation by different receptor-specific mechanisms.
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