The MEKK-JNK pathway is stimulated by alpha1-adrenergic receptor and ras activation and is associated with in vitro and in vivo cardiac hypertrophy.
In neonatal rat ventricular myocytes, stimulation of the alpha1-adrenergic receptor (alpha1-AdrR) activates a program of genetic and morphological changes characterized by transcriptional activation of the atrial natriuretic factor (ANF) gene and enlargement (hypertrophy) of the cells. The low molecular weight GTPase Ras has been established as an important regulator of hypertrophy both in vitro and in vivo. Ras activates a kinase cascade involving Raf, the mitogen-activated protein kinase kinase (MEK), and the extracellular signal-regulated protein kinase (ERK). However, the extent of involvement of this pathway in regulating hypertrophic responses is controversial. We demonstrate here that both alpha1-AdrR stimulation and Ras can also activate the c-Jun NH2-terminal kinase (JNK) in cardiomyocytes. The alpha1-AdrR effect on JNK occurs through a pathway requiring Ras and MEK kinase (MEKK). A constitutively activated mutant of MEKK that preferentially activates JNK, stimulates ANF reporter gene expression, while a dominant negative MEKK mutant inhibits ANF expression induced by PE. Furthermore, JNK activity is increased in the ventricles of mice overexpressing oncogenic Ras, whereas ERK activity is not. These results suggest that the alpha1-AdrR mediates ANF gene expression through a Ras-MEKK-JNK pathway and that activation of this pathway is associated with in vitro and in vivo hypertrophy.
Ramirez
M T
MT
Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA.
Sah
V P
VP
Zhao
X L
XL
Hunter
J J
JJ
Chien
K R
KR
Brown
J H
JH
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D002478:Cells, Cultured; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
D018340:Receptors, Adrenergic, alpha-1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins