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

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 J, 32(10), 1409-24. doi:10.1038/emboj.2013.90.

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 Creators:
Radovanac, K.1, Author
Morgner, J.1, Author
Schulz, J. N.1, Author
Blumbach, K.1, Author
Patterson, C.1, Author
Geiger, T.1, Author
Mann, M.1, Author
Krieg, T.1, Author
Eckes, B.1, Author
Fassler, R.1, Author
Wickström, S. A.1, Author
Affiliations:
1Max Planck Society, ou_persistent13              

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Free keywords: Actins/metabolism Animals Bleomycin/toxicity Cell Movement/*physiology Cells, Cultured Cytoskeleton/metabolism/ultrastructure Extracellular Matrix/metabolism Female Fibroblasts/drug effects/metabolism/pathology Fibrosis/chemically induced/metabolism Focal Adhesions/physiology HSP90 Heat-Shock Proteins/genetics/*metabolism Mice Mice, Inbred C57BL Mice, Mutant Strains Proteasome Endopeptidase Complex/metabolism Protein-Serine-Threonine Kinases/genetics/*metabolism Skin/drug effects/pathology Ubiquitin-Protein Ligases/genetics/*metabolism Ubiquitination
 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 alpha-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.

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 Dates: 2013
 Publication Status: Published in print
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 Identifiers: Other: 23612611
DOI: 10.1038/emboj.2013.90
ISSN: 1460-2075 (Electronic) 0261-4189 (Linking)
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Title: EMBO J
Source Genre: Journal
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Pages: - Volume / Issue: 32 (10) Sequence Number: - Start / End Page: 1409 - 24 Identifier: -