Endothelins stimulate mitogen-activated protein kinase cascade through either ETA or ETB.
Endothelin (ET) has been shown to activate mitogen-activated protein kinase (MAPK). However, it has been unclear which of the ET receptors is coupled to MAPK activation. In the present study, we conducted experiments to determine which ET receptor is linked to MAPK activation. We found that both human ETA and ETB were coupled to the MAPK cascade in ETA or ETB cDNA-transfected Chinese hamster ovary cells. ET-1 was more potent than ET-3 in the activation of p42 MAPK, induction of MAPK kinase (MAPKK) gel retardation and uptake of [3H]thymidine in ETA-transfected cells, whereas sarafotoxin (S6c) showed no stimulatory effect on the kinases and [3H]thymidine uptake. ET-1, ET-3, and S6c had approximately the same potency to activate p42 MAPK, MAPKK gel retardation, and [3H]thymidine uptake in ETB-transfected cells. These data suggest that 1) ET isopeptides, through either ETA or ETB receptors, induce the MAPK cascade as well as cell proliferation; and 2) the different potencies of ET isopeptides for activation of the MAPK cascade and induction of cell growth are mainly due to their different affinities toward ETA and ETB.
Wang
Y
Y
Department of Medicine, Case Western Reserve University, University Hospitals, Cleveland, Ohio 44106.
Rose
P M
PM
Webb
M L
ML
Dunn
M J
MJ
D000818:Animals; D001483:Base Sequence; D016466:CHO Cells / Q000166:cytology / Q000378:metabolism; D002455:Cell Division; D003001:Cloning, Molecular; D006224:Cricetinae; D018076:DNA, Complementary; D016232:Endothelins / Q000494:pharmacology*; D004790:Enzyme Induction; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011869:Radioligand Assay; D017466:Receptors, Endothelin / Q000145:classification / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins; D013936:Thymidine / Q000493:pharmacokinetics
D018076:DNA, Complementary; D016232:Endothelins; D015345:Oligonucleotide Probes; D017466:Receptors, Endothelin; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D013936:Thymidine