title: Epidermal growth factor differentially augments G(i)-mediated stimulation of c-Jun N-terminal kinase activity.
abstract: 1. Signaling networks involving different receptor systems allow extracellular signals to be integrated and transformed into various biological activities. In this report, we studied the activity of the c-Jun N-terminal kinase (JNK) subgroup of mitogen-activated protein kinases (MAPKs), in response to stimulation by G protein-coupled receptors (GPCRs) and co-activation with epithermal growth factor receptor (EGFR). 2. Stimulation of exogenous GPCRs in Cos-7 cells induced JNK activation of different magnitudes depending on their G-protein coupling specificities (G(q)>G(i)>G(s)), and a moderate JNK activation was linked to stimulation of endogenous EGFR by EGF. 3. Co-stimulation with GPCR agonists and EGF resulted in differential augmentation of JNK activities, with G(i)-coupled receptors associated with a synergistic JNK activation upon co-stimulation with EGF, while G(q)- and G(s)-coupled receptors were incapable of triggering this effect. 4. This G(i)/EGF-induced synergistic JNK activation was inhibited by pertussis toxin and AG1478, and may involve Src family tyrosine kinases, PI3 K, Ca(2+)/calmodulin and small GTPases as important intermediates, while Ca(2+) mobilization was triggered by the stimulation of G(q)-coupled receptor or EGF treatment, but not by the G(i)- or G(s)-coupled receptors. 5. Transient expression of Gbetagamma subunits with EGF treatment, or co-activation of exogenous G(i)-coupled receptor with thapsigargin also resulted in a synergistic JNK activation. Activation of G(i)-coupled receptor accompanied with EGF treatment enhanced the expression level and activity of MAPK phosphatase type I, which occurred after the maximal synergistic JNK activation. 6. Our results support a mechanistic model where EGF signaling may differentially regulate the JNK activities triggered by GPCRs of different coupling specificities.
authors.affiliation: Department of Biochemistry, The Biotechnology Research Institute, and The Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong. boyung@ust.hk
authors.forename: Anthony S L
authors.initials: AS
authors.lastname: Chan
authors.forename: Yung H
authors.initials: YH
authors.lastname: Wong
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006723:Hong Kong; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011799:Quinazolines; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000262:Adenylyl Cyclases; D002118:Calcium; D002147:Calmodulin; D004815:Epidermal Growth Factor; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D016755:Proto-Oncogene Proteins c-jun; D011799:Quinazolines; D043562:Receptors, G-Protein-Coupled; D040262:Receptors, Vascular Endothelial Growth Factor; D010738:Type C Phospholipases; D020032:Tyrphostins; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases; C101044:RTKI cpd