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PDGF regulates the actin cytoskeleton through hnRNP-K-mediated activation of the ubiquitin E-3-ligase MIR

Nagano, K., Bornhauser, B.C., Warnasuriya, G., Entwistle, A., Cramer, R., Lindholm, D. and Naaby-Hansen, S. (2006) PDGF regulates the actin cytoskeleton through hnRNP-K-mediated activation of the ubiquitin E-3-ligase MIR. EMBO Journal, 25 (9). pp. 1871-1882. ISSN 0261-4189

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To link to this article DOI: 10.1038/sj.emboj.7601059

Abstract/Summary

PDGF is a potent chemotactic mitogen and a strong inductor of fibroblast motility. In Swiss 3T3 fibroblasts, exposure to PDGF but not EGF or IGF-1 causes a rapid loss of actin stress fibers (SFs) and focal adhesions (FAs), which is followed by the development of retractile dendritic protrusions and induction of motility. The PDGF-specific actin reorganization was blocked by inhibition of Src-kinase and the 26S proteasome. PDGF induced Src-dependent association between the multifunctional transcription/translation regulator hnRNP-K and the mRNA-encoding myosin regulatory light-chain (MRLC)-interacting protein (MIR), a E3-ubiquitin ligase that is MRLC specific. This in turn rapidly increased MIR expression, and led to ubiquitination and proteasome-mediated degradation of MRLC. Downregulation of MIR by RNA muting prevented the reorganization of actin structures and severely reduced the migratory and wound-healing potential of PDGF-treated cells. The results show that activation of MIR and the resulting removal of diphosphorylated MRLC are essential for PDGF to instigate and maintain control over the actin-myosin-based contractile system in Swiss 3T3 fibroblasts. The PDGF induced protein destabilization through the regulation of hnRNP-K controlled ubiquitin-ligase translation identifies a novel pathway by which external stimuli can regulate phenotypic development through rapid, organelle-specific changes in the activity and stability of cytoskeletal regulators.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > Department of Chemistry
ID Code:11524
Uncontrolled Keywords:focal adhesions, hnRNP-K, MIR, PDGF, ubiquitin , SMOOTH-MUSCLE MYOSIN, FOCAL ADHESION KINASE, LIGHT-CHAIN, GROWTH-FACTOR, RHO-KINASE, TYROSINE PHOSPHORYLATION, NEURITE OUTGROWTH, PROTEIN-KINASE, RNA TARGETS, CROSS-TALK

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