Hsp90 increases LIM kinase activity by promoting its homo-dimerization.

Rong Li, Juliana Soosairajah, Daniel Harari, Ami Citri, John Timothy Price, Hooi Ling Ng, Craig J Morton, Michael W Parker, Yosef Yarden, Ora Bernard

Research output: Contribution to journalArticleResearchpeer-review

Abstract

LIM kinase 1 (LIMK1) is a serine protein kinase that regulates the actin cytoskeleton by phosphorylation and inactivation of actin depolymerizing factor cofilin. LIMK1 activity is regulated by the Rho-GTPases via their serine/threonine kinase effectors Rho-kinase and p21-activated kinases 1 and 4 that phosphorylate LIMK1 on threonine 508 in its activation loop. The purpose of this study was to elucidate the pathway leading to the stability of LIMK1, a protein with a half-life of approximately 20 h. Because the half-life of kinase-dead LIMK1 is only 4 h, it is suggestive that trans- or auto-phosphorylation is responsible for the stabilization of LIMK1. Using known Hsp90 inhibitors, we have shown that the half-life of LIMK1 in cells depends on the presence of active Hsp90. Furthermore, endogenous LIMK1 coimmunoprecipitated with endogenous Hsp90 and this interaction promoted LIMK1 homodimer formation as seen by cross-linking experiments. Hsp90 binds LIMK1 via a recognition sequence within the LIMK1 kinase domain, homologous to that of ErbB-2. Mutation of a proline residue within this sequence to glutamic acid reduces its interaction with Hsp90, inhibits homodimer formation, and reduces its half-life to 4 h. These findings implicate Hsp90 in the stabilization of LIMK1 by promoting homodimer formation and transphosphorylation.
Original languageEnglish
Pages (from-to)1218 - 1220
Number of pages2
JournalFASEB Journal
Volume20
Issue number8
DOIs
Publication statusPublished - 2006

Cite this

Li, R., Soosairajah, J., Harari, D., Citri, A., Price, J. T., Ng, H. L., ... Bernard, O. (2006). Hsp90 increases LIM kinase activity by promoting its homo-dimerization. FASEB Journal, 20(8), 1218 - 1220. https://doi.org/10.1096/fj.05-5258fje
Li, Rong ; Soosairajah, Juliana ; Harari, Daniel ; Citri, Ami ; Price, John Timothy ; Ng, Hooi Ling ; Morton, Craig J ; Parker, Michael W ; Yarden, Yosef ; Bernard, Ora. / Hsp90 increases LIM kinase activity by promoting its homo-dimerization. In: FASEB Journal. 2006 ; Vol. 20, No. 8. pp. 1218 - 1220.
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abstract = "LIM kinase 1 (LIMK1) is a serine protein kinase that regulates the actin cytoskeleton by phosphorylation and inactivation of actin depolymerizing factor cofilin. LIMK1 activity is regulated by the Rho-GTPases via their serine/threonine kinase effectors Rho-kinase and p21-activated kinases 1 and 4 that phosphorylate LIMK1 on threonine 508 in its activation loop. The purpose of this study was to elucidate the pathway leading to the stability of LIMK1, a protein with a half-life of approximately 20 h. Because the half-life of kinase-dead LIMK1 is only 4 h, it is suggestive that trans- or auto-phosphorylation is responsible for the stabilization of LIMK1. Using known Hsp90 inhibitors, we have shown that the half-life of LIMK1 in cells depends on the presence of active Hsp90. Furthermore, endogenous LIMK1 coimmunoprecipitated with endogenous Hsp90 and this interaction promoted LIMK1 homodimer formation as seen by cross-linking experiments. Hsp90 binds LIMK1 via a recognition sequence within the LIMK1 kinase domain, homologous to that of ErbB-2. Mutation of a proline residue within this sequence to glutamic acid reduces its interaction with Hsp90, inhibits homodimer formation, and reduces its half-life to 4 h. These findings implicate Hsp90 in the stabilization of LIMK1 by promoting homodimer formation and transphosphorylation.",
author = "Rong Li and Juliana Soosairajah and Daniel Harari and Ami Citri and Price, {John Timothy} and Ng, {Hooi Ling} and Morton, {Craig J} and Parker, {Michael W} and Yosef Yarden and Ora Bernard",
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Li, R, Soosairajah, J, Harari, D, Citri, A, Price, JT, Ng, HL, Morton, CJ, Parker, MW, Yarden, Y & Bernard, O 2006, 'Hsp90 increases LIM kinase activity by promoting its homo-dimerization.', FASEB Journal, vol. 20, no. 8, pp. 1218 - 1220. https://doi.org/10.1096/fj.05-5258fje

Hsp90 increases LIM kinase activity by promoting its homo-dimerization. / Li, Rong; Soosairajah, Juliana; Harari, Daniel; Citri, Ami; Price, John Timothy; Ng, Hooi Ling; Morton, Craig J; Parker, Michael W; Yarden, Yosef; Bernard, Ora.

In: FASEB Journal, Vol. 20, No. 8, 2006, p. 1218 - 1220.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Hsp90 increases LIM kinase activity by promoting its homo-dimerization.

AU - Li, Rong

AU - Soosairajah, Juliana

AU - Harari, Daniel

AU - Citri, Ami

AU - Price, John Timothy

AU - Ng, Hooi Ling

AU - Morton, Craig J

AU - Parker, Michael W

AU - Yarden, Yosef

AU - Bernard, Ora

PY - 2006

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N2 - LIM kinase 1 (LIMK1) is a serine protein kinase that regulates the actin cytoskeleton by phosphorylation and inactivation of actin depolymerizing factor cofilin. LIMK1 activity is regulated by the Rho-GTPases via their serine/threonine kinase effectors Rho-kinase and p21-activated kinases 1 and 4 that phosphorylate LIMK1 on threonine 508 in its activation loop. The purpose of this study was to elucidate the pathway leading to the stability of LIMK1, a protein with a half-life of approximately 20 h. Because the half-life of kinase-dead LIMK1 is only 4 h, it is suggestive that trans- or auto-phosphorylation is responsible for the stabilization of LIMK1. Using known Hsp90 inhibitors, we have shown that the half-life of LIMK1 in cells depends on the presence of active Hsp90. Furthermore, endogenous LIMK1 coimmunoprecipitated with endogenous Hsp90 and this interaction promoted LIMK1 homodimer formation as seen by cross-linking experiments. Hsp90 binds LIMK1 via a recognition sequence within the LIMK1 kinase domain, homologous to that of ErbB-2. Mutation of a proline residue within this sequence to glutamic acid reduces its interaction with Hsp90, inhibits homodimer formation, and reduces its half-life to 4 h. These findings implicate Hsp90 in the stabilization of LIMK1 by promoting homodimer formation and transphosphorylation.

AB - LIM kinase 1 (LIMK1) is a serine protein kinase that regulates the actin cytoskeleton by phosphorylation and inactivation of actin depolymerizing factor cofilin. LIMK1 activity is regulated by the Rho-GTPases via their serine/threonine kinase effectors Rho-kinase and p21-activated kinases 1 and 4 that phosphorylate LIMK1 on threonine 508 in its activation loop. The purpose of this study was to elucidate the pathway leading to the stability of LIMK1, a protein with a half-life of approximately 20 h. Because the half-life of kinase-dead LIMK1 is only 4 h, it is suggestive that trans- or auto-phosphorylation is responsible for the stabilization of LIMK1. Using known Hsp90 inhibitors, we have shown that the half-life of LIMK1 in cells depends on the presence of active Hsp90. Furthermore, endogenous LIMK1 coimmunoprecipitated with endogenous Hsp90 and this interaction promoted LIMK1 homodimer formation as seen by cross-linking experiments. Hsp90 binds LIMK1 via a recognition sequence within the LIMK1 kinase domain, homologous to that of ErbB-2. Mutation of a proline residue within this sequence to glutamic acid reduces its interaction with Hsp90, inhibits homodimer formation, and reduces its half-life to 4 h. These findings implicate Hsp90 in the stabilization of LIMK1 by promoting homodimer formation and transphosphorylation.

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16641196

U2 - 10.1096/fj.05-5258fje

DO - 10.1096/fj.05-5258fje

M3 - Article

VL - 20

SP - 1218

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JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

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ER -