δ-Opioid receptors activate ERK/MAP kinase via integrin-stimulated receptor tyrosine kinases

摘要: Integrin-mediated cell adherence to extracellular matrix proteins results in stimulation of ERK1/2 activity, a mechanism involving focal adhesion tyrosine kinases (pp125FAK, Pyk-2) and epidermal growth factor receptors (EGFRs). G protein-coupled (GPCRs) may also mediate activation an integrin-dependent manner, the underlying signaling which still remains unclear. Here we demonstrate that delta-opioid receptor (DOR), typical GPCR, stimulates activity HEK293 cells via integrin-mediated transactivation EGFR function. Inhibition integrin by RGDT peptides, cytochalasin, keeping suspension culture both blocked [D-Ala(2), D-Leu(5)]enkephalin (DADLE)- etorphine-stimulated activity. Integrin-dependent does not involve FAK/Pyk-2, because over-expression FAK/Pyk-2 inhibitor SOCS-3 failed attenuate DOR signaling. Exposure inhibitors AG1478 BPIQ-I DOR-mediated activation. Because peptides prevented activation, present findings indicate DOR-stimulated is mediated integrin-stimulated EGFRs. Further studies with phospholipase C (PLC) U73122 ET-18-OCH(3) revealed opioid-stimulated sensitive PLC. In contrast, function appears be dependent on PKC-delta, as indicated rottlerin siRNA knock-down. A similar pathway was observed for NG108-15 cells, neuronal line endogenously expressing DOR. these nerve TrkA replaces connecting DOR-activated integrins Ras/Raf/ERK1/2 pathway. Together, data describe alternative transactivates associated mitogen-activated protein kinase cascade manner.