Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response
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Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response. / Radovanac, Korana; Morgner, Jessica; Schulz, Jan-Niklas; Blumbach, Katrin; Patterson, Cam; Geiger, Tamar; Mann, Matthias; Krieg, Thomas; Eckes, Beate; Fässler, Reinhard; Wickström, Sara A.
In: E M B O Journal, Vol. 32, No. 10, 15.05.2013, p. 1409-24.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response
AU - Radovanac, Korana
AU - Morgner, Jessica
AU - Schulz, Jan-Niklas
AU - Blumbach, Katrin
AU - Patterson, Cam
AU - Geiger, Tamar
AU - Mann, Matthias
AU - Krieg, Thomas
AU - Eckes, Beate
AU - Fässler, Reinhard
AU - Wickström, Sara A
PY - 2013/5/15
Y1 - 2013/5/15
N2 - 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.
AB - 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.
KW - Actins
KW - Animals
KW - Bleomycin
KW - Cell Movement
KW - Cells, Cultured
KW - Cytoskeleton
KW - Extracellular Matrix
KW - Female
KW - Fibroblasts
KW - Fibrosis
KW - Focal Adhesions
KW - HSP90 Heat-Shock Proteins
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Mutant Strains
KW - Proteasome Endopeptidase Complex
KW - Protein-Serine-Threonine Kinases
KW - Skin
KW - Ubiquitin-Protein Ligases
KW - Ubiquitination
U2 - 10.1038/emboj.2013.90
DO - 10.1038/emboj.2013.90
M3 - Journal article
C2 - 23612611
VL - 32
SP - 1409
EP - 1424
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 10
ER -
ID: 88585179