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PDGF regulates the actin cytoskeleton through hnRNP‐K‐mediated activation of the ubiquitin E 3 ‐ligase MIR
Author(s) -
Nagano Kohji,
Bornhauser Beat C,
Warnasuriya Gayathri,
Entwistle Alan,
Cramer Rainer,
Lindholm Dan,
NaabyHansen Soren
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601059
Subject(s) - biology , ubiquitin ligase , ubiquitin , microbiology and biotechnology , cytoskeleton , actin cytoskeleton , actin , biochemistry , cell , gene
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 E 3 ‐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.