RGD Reference Report - Endothelin-1 activates mesangial cell ERK1/2 via EGF-receptor transactivation and caveolin-1 interaction. - Rat Genome Database

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Endothelin-1 activates mesangial cell ERK1/2 via EGF-receptor transactivation and caveolin-1 interaction.

Authors: Hua, H  Munk, S  Whiteside, CI 
Citation: Hua H, etal., Am J Physiol Renal Physiol 2003 Feb;284(2):F303-12.
RGD ID: 727457
Pubmed: PMID:12388423   (View Abstract at PubMed)
DOI: DOI:10.1152/ajprenal.00127.2002   (Journal Full-text)

Endothelin-1 (ET-1) stimulates glomerular mesangial cell proliferation and extracellular matrix protein transcription through an ERK1/2-dependent pathway. In this study, we determined whether ET-1 activation of glomerular mesangial cell ERK1/2 is mediated through EGF receptor (EGF-R) transactivation and whether intact caveolae are required. We showed that ET-1 stimulated tyrosine phosphorylation of the EGF-R in primary cultured, growth-arrested rat mesangial cells. In response to ET-1, ERK1/2 phosphorylation was increased by 27 +/- 1-fold and attenuated by AG-1478, a specific EGF-R inhibitor, to 9 +/- 1-fold. Moreover, filipin III and beta-cyclodextrin, two cholesterol-depleting drugs known to disrupt caveolae, significantly reduced ET-1-induced phosphorylation of ERK1/2. In addition, preincubation of mesangial cells with a myristoylated peptide that binds to the caveolin-1 scaffolding domain diminished ET-1 activation of ERK1/2. ET-1 caused interaction of caveolin-1 with phosphorylated ERK1/2 identified by coimmunoprecipitation. Activation of ERK1/2 and its interaction with caveolin-1 were reduced by AG-1478, beta-cyclodextrin, or inhibition of PKC. Phosphorylated ERK1/2 localized at focal adhesion complexes along with phospho-caveolin-1, suggesting specific sites of compartmentalization of these signaling molecules. Hence, ET-1 activates mesangial cell ERK1/2 predominantly through a pathway involving EGF-R transactivation, leading to a mechanism involving attachment to caveolin-1, presumably in caveolae.




Biological Process

  
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Original Reference(s)
Edn1Ratintracellular signal transduction  IDA  RGD 


Genes (Rattus norvegicus)
Edn1  (endothelin 1)

Gene Cav1 caveolin 1 Rattus norvegicus
Gene Egfr epidermal growth factor receptor Rattus norvegicus
Gene Mapk1 mitogen activated protein kinase 1 Rattus norvegicus
Gene Mapk3 mitogen activated protein kinase 3 Rattus norvegicus
Gene Tnf tumor necrosis factor Rattus norvegicus