Hsp90 increases LIM kinase activity by promoting its homo-dimerization
- Author(s)
- Li, R; Soosairajah, J; Harari, D; Citri, A; Price, J; Ng, HL; Morton, CJ; Parker, MW; Yarden, Y; Bernard, O;
- Details
- Publication Year 2006-06,Volume 20,Issue #8,Page 1218-+
- Journal Title
- FASEB JOURNAL
- Publication Type
- Journal Article
- 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 similar to 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.
- Publisher
- FEDERATION AMER SOC EXP BIOL
- Keywords
- ACTIN DYNAMICS; CHAPERONE COMPLEX; PROTEIN; COFILIN; PHOSPHORYLATION; CANCER; DOMAIN; ERBB-2/HER2; ACTIVATION; REGULATOR
- Publisher's Version
- https://doi.org/10.1096/fj.05-5258fje
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2006-06-01 12:00:00