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

Korana Radovanac; Jessica Morgner; Jan-Niklas Schulz; Katrin Blumbach; Cam Patterson; Tamar Geiger; Matthias Mann; Thomas Krieg; Beate Eckes; Reinhard Fässler; Sara A Wickström

doi:10.1038/emboj.2013.90

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

Korana Radovanac, Jessica Morgner, Jan-Niklas Schulz, Katrin Blumbach, Cam Patterson, Tamar Geiger, Matthias Mann, Thomas Krieg, Beate Eckes, Reinhard Fässler, Sara A Wickström

45 Citations (Scopus)

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.

Original language	English
Journal	E M B O Journal
Volume	32
Issue number	10
Pages (from-to)	1409-24
Number of pages	16
ISSN	0261-4189
DOIs	https://doi.org/10.1038/emboj.2013.90
Publication status	Published - 15 May 2013
Externally published	Yes

Keywords

Actins
Animals
Bleomycin
Cell Movement
Cells, Cultured
Cytoskeleton
Extracellular Matrix
Female
Fibroblasts
Fibrosis
Focal Adhesions
HSP90 Heat-Shock Proteins
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Proteasome Endopeptidase Complex
Protein-Serine-Threonine Kinases
Skin
Ubiquitin-Protein Ligases
Ubiquitination

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10.1038/emboj.2013.90

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

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.",

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author = "Korana Radovanac and Jessica Morgner and Jan-Niklas Schulz and Katrin Blumbach and Cam Patterson and Tamar Geiger and Matthias Mann and Thomas Krieg and Beate Eckes and Reinhard F{\"a}ssler and Wickstr{\"o}m, {Sara A}",

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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

SN - 0261-4189

VL - 32

SP - 1409

EP - 1424

JO - E M B O Journal

JF - E M B O Journal

IS - 10

ER -

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

Abstract

Keywords

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