Neuropeptide Y receptor mediates activation of ERK1/2 via transactivation of the IGF receptor.

S. Lecat , L. Belemnaba (1) , J.L. Galzi , B. Bucher (1)

1 LBP - Laboratoire de Biophotonique et Pharmacologie - UMR 7213

Neuropeptide Y binds to G-protein coupled receptors whose action results in inhibition of adenylyl cyclase activity. Using HEK293 cells stably expressing the native neuropeptide Y Y-1 receptors, we found that the NPY agonist elicits a transient phosphorylation of the extracellular signal-regulated kinases (ERK1/2). We first show that ERK1/2 activation following Y-1 receptor stimulation is dependent on heterotrimeric G(i/o) since it is completely inhibited by pre-treatment with pertussis toxin. In addition, ERK1/2 activation is internalization-independent since mutant Y-1 receptors unable to recruit beta-arrestins, can still activate ERK signaling to the same extent as wild-type receptors. We next show that this activation of the MAPK pathway is inhibited by the MEK inhibitor U0126, is not dependent on calcium signaling at the Y-1 receptor (no effect upon inhibition of phospholipase C, protein kinase C or protein kinase D) but instead dependent on G beta/gamma and associated signaling pathways that activate PI3-kinase. Although inhibition of the epidermal-growth factor receptor tyrosine kinase did not influence NPY-induced ERK1/2 activation, we show that the inhibition of insulin growth factor receptor IGFR by AG1024 completely blocks activation of ERK1/2 by the Y-1 receptor. This G beta/gamma-PI3K-AG1024-sensitive pathway does not involve activation of IGFR through the release of a soluble ligand by metalloproteinases since it is not affected by the metalloproteinase inhibitor marimastat. Finally, we found that a similar pathway, sensitive to wortmannin-AG1024 but insensitive to marimastat, is implicated in activation of ERK signaling in HEK293 cells by endogenously expressed GPCRs coupled to Gq-protein (muscarinic M3 receptors) or coupled to Gs-protein (endothelin ETB receptors). Our analysis is the first to show that beta-arrestin recruitment to the NPY Y-1 receptor is not necessary for MAPK activation by this receptor but that transactivation of the IGFR receptor is required

Domaines: Sciences du Vivant [q-bio]

S. Lecat, L. Belemnaba, J.L. Galzi, B. Bucher. Neuropeptide Y receptor mediates activation of ERK1/2 via transactivation of the IGF receptor.. Cellular Signalling, 2015, 27 (7), pp.1297-1304. ⟨10.1016/j.cellsig.2015.03.016⟩. ⟨hal-01141606⟩