Dopamine activates ERKs in alveolar epithelial cells via Ras-PKC-dependent and Grb2/Sos-independent mechanisms.
Recently it has been described that dopamine (DA), via dopaminergic type 2 receptors (D(2)R), activates the mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK/ERK) proteins in alveolar epithelial cells (AEC), which results in the upregulation of Na(+)-K(+)-ATPase. In the present report, we used AEC to investigate the signaling pathway that links DA with ERK activation. Incubation of AEC with DA resulted in rapid and transient stimulation of ERK activity, which was mediated by Ras proteins and the serine/threonine kinase Raf-1. Pretreatment of AEC with Src homology 3 binding peptide, which blocks the interaction between Grb2 and Sos, did not prevent DA activation of ERK. Diacylglycerol (DAG)-dependent protein kinase C (PKC) isoenzymes, involved in the DA-mediated activation of ERK proteins as pretreatment with either bisindolylmaleimide or Ro-31-8220, prevented the phosphorylation of Elk-1, and quinpirole, a D(2)R activator, stimulates the translocation of PKCepsilon. Together, the data suggest that DA activated MAPK/ERK via Ras, Raf-1 kinase, and DAG-dependent PKC isoenzymes, but, importantly and contrary to the classical model, this pathway did not involve the Grb2-Sos complex formation.
Guerrero
Carmen
C
Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Pesce
Liuska
L
Lecuona
Emilia
E
Ridge
Karen M
KM
Sznajder
Jacob I
JI
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology*; D051380:GRB2 Adaptor Protein; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology; D020839:Son of Sevenless Protein, Drosophila / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D018631:ras Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D004075:Diglycerides; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D011506:Proteins; D020839:Son of Sevenless Protein, Drosophila; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D004298:Dopamine