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Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons78533

Radovanac,  Korana
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons77998

Geiger,  Tamar
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78356

Mann,  Matthias
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons77945

Fässler,  Reinhard
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Radovanac, K., Morgner, J., Schulz, J.-N., Blumbach, K., Patterson, C., Geiger, T., et al. (2013). Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response. EMBO JOURNAL, 32(10), 1409-1424. doi:10.1038/emboj.2013.90.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-1152-A
Abstract
Integrin-linked kinase (ILK) is an adaptor protein required to establish and maintain the connection between integrins and the actin cytoskeleton. This linkage is essential for generating force between the extracellular matrix (ECM) and the cell during migration and matrix remodelling. The mechanisms by which ILK stability and turnover are regulated are unknown. Here we report that the E3 ligase CHIP-heat shock protein 90 (Hsp90) axis regulates ILK turnover in fibroblasts. The chaperone Hsp90 stabilizes ILK and facilitates the interaction of ILK with a-parvin. When Hsp90 activity is blocked, ILK is ubiquitinated by CHIP and degraded by the proteasome, resulting in impaired fibroblast migration and a dramatic reduction in the fibrotic response to bleomycin in mice. Together, our results uncover how Hsp90 regulates ILK stability and identify a potential therapeutic strategy to alleviate fibrotic diseases.