Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response
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 mechanism...
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| Veröffentlicht in: | The EMBO journal 2013-05, Vol.32 (10), p.1409-1424 |
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| creator | Radovanac, Korana Morgner, Jessica Schulz, Jan-Niklas Blumbach, Katrin Patterson, Cam Geiger, Tamar Mann, Matthias Krieg, Thomas Eckes, Beate Fässler, Reinhard Wickström, Sara A |
| description | 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 α‐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.
The ILK–PINCH–parvin complex connects integrins to actin filaments, generating force for cell migration. In fibroblasts, Hsp90 promotes complex formation while its inhibition causes CHIP‐mediated ILK ubiquitination and degradation, impaired migration, and an alleviated fibrotic response in mice. |
| doi_str_mv | 10.1038/emboj.2013.90 |
| format | Article |
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The ILK–PINCH–parvin complex connects integrins to actin filaments, generating force for cell migration. In fibroblasts, Hsp90 promotes complex formation while its inhibition causes CHIP‐mediated ILK ubiquitination and degradation, impaired migration, and an alleviated fibrotic response in mice.</description><identifier>ISSN: 0261-4189</identifier><identifier>EISSN: 1460-2075</identifier><identifier>DOI: 10.1038/emboj.2013.90</identifier><identifier>PMID: 23612611</identifier><identifier>CODEN: EMJODG</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Actins - metabolism ; Animals ; Bleomycin - toxicity ; Cell adhesion & migration ; Cell Movement - physiology ; Cells, Cultured ; Cytoskeleton - metabolism ; Cytoskeleton - ultrastructure ; EMBO05 ; EMBO31 ; extracellular matrix ; Extracellular Matrix - metabolism ; Female ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Fibroblasts - pathology ; fibrosis ; Fibrosis - chemically induced ; Fibrosis - metabolism ; Focal Adhesions - physiology ; Gene expression ; Heat shock proteins ; Hsp90 ; HSP90 Heat-Shock Proteins - genetics ; HSP90 Heat-Shock Proteins - metabolism ; integrin ; integrin-linked kinase ; Kinases ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Molecular biology ; Proteasome Endopeptidase Complex - metabolism ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Skin - drug effects ; Skin - pathology ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination</subject><ispartof>The EMBO journal, 2013-05, Vol.32 (10), p.1409-1424</ispartof><rights>European Molecular Biology Organization 2013</rights><rights>Copyright © 2013 European Molecular Biology Organization</rights><rights>Copyright Nature Publishing Group May 15, 2013</rights><rights>Copyright © 2013, European Molecular Biology Organization 2013 European Molecular Biology Organization</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5380-2f44a232cfbb7b35c7158078cabedb0d0a10226220a4aaae511c9fb5db09df9e3</citedby><cites>FETCH-LOGICAL-c5380-2f44a232cfbb7b35c7158078cabedb0d0a10226220a4aaae511c9fb5db09df9e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655474/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655474/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,1417,1433,27924,27925,41120,42189,45574,45575,46409,46833,51576,53791,53793</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.1038/emboj.2013.90$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23612611$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Radovanac, Korana</creatorcontrib><creatorcontrib>Morgner, Jessica</creatorcontrib><creatorcontrib>Schulz, Jan-Niklas</creatorcontrib><creatorcontrib>Blumbach, Katrin</creatorcontrib><creatorcontrib>Patterson, Cam</creatorcontrib><creatorcontrib>Geiger, Tamar</creatorcontrib><creatorcontrib>Mann, Matthias</creatorcontrib><creatorcontrib>Krieg, Thomas</creatorcontrib><creatorcontrib>Eckes, Beate</creatorcontrib><creatorcontrib>Fässler, Reinhard</creatorcontrib><creatorcontrib>Wickström, Sara A</creatorcontrib><title>Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response</title><title>The EMBO journal</title><addtitle>EMBO J</addtitle><addtitle>EMBO J</addtitle><description>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 α‐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.
The ILK–PINCH–parvin complex connects integrins to actin filaments, generating force for cell migration. In fibroblasts, Hsp90 promotes complex formation while its inhibition causes CHIP‐mediated ILK ubiquitination and degradation, impaired migration, and an alleviated fibrotic response in mice.</description><subject>Actins - metabolism</subject><subject>Animals</subject><subject>Bleomycin - toxicity</subject><subject>Cell adhesion & migration</subject><subject>Cell Movement - physiology</subject><subject>Cells, Cultured</subject><subject>Cytoskeleton - metabolism</subject><subject>Cytoskeleton - ultrastructure</subject><subject>EMBO05</subject><subject>EMBO31</subject><subject>extracellular matrix</subject><subject>Extracellular Matrix - metabolism</subject><subject>Female</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Fibroblasts - pathology</subject><subject>fibrosis</subject><subject>Fibrosis - chemically induced</subject><subject>Fibrosis - metabolism</subject><subject>Focal Adhesions - physiology</subject><subject>Gene expression</subject><subject>Heat shock proteins</subject><subject>Hsp90</subject><subject>HSP90 Heat-Shock Proteins - genetics</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>integrin</subject><subject>integrin-linked kinase</subject><subject>Kinases</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Mutant Strains</subject><subject>Molecular biology</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Skin - drug effects</subject><subject>Skin - pathology</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - 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J</addtitle><date>2013-05-15</date><risdate>2013</risdate><volume>32</volume><issue>10</issue><spage>1409</spage><epage>1424</epage><pages>1409-1424</pages><issn>0261-4189</issn><eissn>1460-2075</eissn><coden>EMJODG</coden><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 α‐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.
The ILK–PINCH–parvin complex connects integrins to actin filaments, generating force for cell migration. In fibroblasts, Hsp90 promotes complex formation while its inhibition causes CHIP‐mediated ILK ubiquitination and degradation, impaired migration, and an alleviated fibrotic response in mice.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>23612611</pmid><doi>10.1038/emboj.2013.90</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| source | Springer Nature OA Free Journals |
| subjects | Actins - metabolism Animals Bleomycin - toxicity Cell adhesion & migration Cell Movement - physiology Cells, Cultured Cytoskeleton - metabolism Cytoskeleton - ultrastructure EMBO05 EMBO31 extracellular matrix Extracellular Matrix - metabolism Female Fibroblasts - drug effects Fibroblasts - metabolism Fibroblasts - pathology fibrosis Fibrosis - chemically induced Fibrosis - metabolism Focal Adhesions - physiology Gene expression Heat shock proteins Hsp90 HSP90 Heat-Shock Proteins - genetics HSP90 Heat-Shock Proteins - metabolism integrin integrin-linked kinase Kinases Mice Mice, Inbred C57BL Mice, Mutant Strains Molecular biology Proteasome Endopeptidase Complex - metabolism Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Skin - drug effects Skin - pathology Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Ubiquitination |
| title | Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response |
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