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Differential requirement for MEK/ERK and SMAD signaling in PAI-1 and CTGF expression in response to microtubule disruption
- Source :
- Cellular Signalling. 21:986-995
- Publication Year :
- 2009
- Publisher :
- Elsevier BV, 2009.
-
Abstract
- Colchicine and nocodazole, both established microtubule disruptors, are useful tools to investigate cytoskeletal-dependent signaling cascades and the associated downstream transcriptional targets. Since cytoskeletal events impact pathophysiologic consequences in the vascular system, the signaling requirements underlying colchicine-stimulated expression of PAI-1 and CTGF, two prominent cell deformation-sensitive fibrosis-initiating proteins, were evaluated in vascular smooth muscle cells. Microtubule disruption rapidly induced EGFR transactivation (at the src kinase-sensitive EGFR(Y845) site) in a ROS-dependent manner. Genetic deficiency of EGFR, inhibition of EGFR signaling with AG1478 or introduction of a kinase-deficient EGFR construct effectively blocked colchicine-stimulated PAI-1 and CTGF expression. MEK/ERK involvement downstream of ROS generation was critical for PAI-1, but not CTGF, expression following cytoskeletal perturbation suggesting bifurcation of signaling pathways downstream of EGFR activation. Colchicine also stimulated SMAD2/3 phosphorylation by a Rho/ROCK-dependent mechanism independent of TGF-beta1 release or receptor activity. Rho/ROCK signaling initiated by tubulin network collapse was required for both CTGF and PAI-1 induction. Colchicine-initiated SMAD3 phosphorylation, however, was essential for PAI-1, but not CTGF, expression further highlighting divergence of signaling events downstream of Rho/ROCK that mediate microtubule deformation-associated changes in profibrotic gene transcription.
- Subjects :
- Transcriptional Activation
MAPK/ERK pathway
MAP Kinase Signaling System
Proto-Oncogene Proteins pp60(c-src)
Smad Proteins
SMAD
Biology
Microtubules
Article
Mice
chemistry.chemical_compound
Microtubule
Plasminogen Activator Inhibitor 1
Animals
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Cytoskeleton
Mitogen-Activated Protein Kinase Kinases
rho-Associated Kinases
Nocodazole
Connective Tissue Growth Factor
Cell Biology
Tubulin Modulators
Cell biology
Enzyme Activation
ErbB Receptors
CTGF
chemistry
Cancer research
Signal transduction
Colchicine
Reactive Oxygen Species
rhoA GTP-Binding Protein
Subjects
Details
- ISSN :
- 08986568
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Cellular Signalling
- Accession number :
- edsair.doi.dedup.....489f8a179cba97fa13cac31895753d6b