Receptor-specific regulation of ERK1/2 activation by members of the "free fatty acid receptor" family.
BACKGROUND
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 G(i/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.


CONCLUSIONS
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.
Novartis Institutes for BioMedical Research Basel, Center for Proteomic Chemistry, Basel, Switzerland.
Sandra
S
Seljeset
Sandra
S
Siehler
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004789:Enzyme Activation; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D048053:Mitogen-Activated Protein Kinase 6 / Q000378:metabolism*; D008954:Models, Biological; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048053:Mitogen-Activated Protein Kinase 6; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D048051:p38 Mitogen-Activated Protein Kinases; C473103:FFAR2 protein, human; C473034:FFAR1 protein, human; C106262:FFAR3 protein, human