LIM kinase 1, a key regulator of actin dynamics, is widely expressed in embryonic and adult tissues

Foletta, Victoria C.; Moussi, Nathalie; Sarmiere, Patrick D.; Bamburg, James R.; Bernard, Ora

doi:10.1016/j.yexcr.2003.11.024

Cited by 88 publications

(71 citation statements)

References 43 publications

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“…In fact, A␤ dystrophy requires aberrant activation of focal adhesion proteins, including Paxillin (Grace and Busciglio, 2003), activation of which could also depend on A␤PP or integrins, through their interaction with different cytoplasmic proteins (Sabo et al, 2001b;Zambrano et al, 2001;Martin et al, 2002). Interestingly, LIMK1 and its activator PAK have been shown to colocalize with Paxillin in focal adhesions (Foletta et al, 2004;Chen et al, 2005). Thus, LIMK1 may be a key downstream effector for A␤ fibril-induced actin remodeling in the aberrant focal adhesion complex, providing the initial forces to remodel neuronal shape around A␤ deposits.…”

Section: Discussionmentioning

confidence: 99%

“…LIM kinase 1 (LIMK1) phosphorylates and thereby inhibits ADF/cofilin (Arber et al, 1998). LIMK1 is widely expressed in tissues, including the nervous system (Proschel et al, 1995;Foletta et al, 2004), and its activity modulates neuritogenesis and synaptic plasticity (Meng et al, 2002;Endo et al, 2003;Rosso et al, 2004). LIMK1 is a key downstream effector of the Rho family of small GTPases and is activated by phosphorylation on Thr508 by Rho kinase ROCK, or by Rac-Cdc42 p21-activated kinase (PAK) (Edwards et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of Actin-Depolymerizing Factor/Cofilin by LIM-Kinase Mediates Amyloid -Induced Degeneration: A Potential Mechanism of Neuronal Dystrophy in Alzheimer's Disease

Heredia

Helguera

Olmos

et al. 2006

Journal of Neuroscience

168

127

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Deposition of fibrillar amyloid ␤ (fA␤) plays a critical role in Alzheimer's disease (AD). We have shown recently that fA␤-induced dystrophy requires the activation of focal adhesion proteins and the formation of aberrant focal adhesion structures, suggesting the activation of a mechanism of maladaptative plasticity in AD. Focal adhesions are actin-based structures that provide a structural link between the extracellular matrix and the cytoskeleton. To gain additional insight in the molecular mechanism of neuronal degeneration in AD, here we explored the involvement of LIM kinase 1 (LIMK1), actin-depolymerizing factor (ADF), and cofilin in A␤-induced dystrophy. ADF/cofilin are actin-binding proteins that play a central role in actin filament dynamics, and LIMK1 is the kinase that phosphorylates and thereby inhibits ADF/cofilin. Our data indicate that treatment of hippocampal neurons with fA␤ increases the level of Ser3-phosphorylated ADF/cofilin and Thr508-phosphorylated LIMK1 (P-LIMK1), accompanied by a dramatic remodeling of actin filaments, neuritic dystrophy, and neuronal cell death. A synthetic peptide, S3 peptide, which acts as a specific competitor for ADF/cofilin phosphorylation by LIMK1, inhibited fA␤-induced ADF/cofilin phosphorylation, preventing actin filament remodeling and neuronal degeneration, indicating the involvement of LIMK1 in A␤-induced neuronal degeneration in vitro. Immunofluorescence analysis of AD brain showed a significant increase in the number of P-LIMK1-positive neurons in areas affected with AD pathology. P-LIMK1-positive neurons also showed early signs of AD pathology, such as intracellular A␤ and pretangle phosphorylated tau. Thus, LIMK1 activation may play a key role in AD pathology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phosphorylation of Actin-Depolymerizing Factor/Cofilin by LIM-Kinase Mediates Amyloid -Induced Degeneration: A Potential Mechanism of Neuronal Dystrophy in Alzheimer's Disease

Heredia

Helguera

Olmos

et al. 2006

Journal of Neuroscience

168

127

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“…pBABE-Flag-TPPP1 [6], pBABE-Flag-LIMK1, pBABE-FLag-LIMK1-DN [12], myc-cofilin, myc-cofilin S3A and myc-cofilin S3D [13] plasmids were generated as previously described. pcDNA3-Flag-HDAC6 was obtained from Addgene and was originally cloned as described [14].…”

Section: Plasmid Constructsmentioning

confidence: 99%

“…Cleared lysates were incubated with ~2 μg of isotype control, anti-HDAC6 (Sigma-Aldrich), anti-TPPP1 [6] or anti-LIMK1 [12] antibodies and Protein A/G sepharose overnight at 4˚C with rotation. Immunoprecipitated (IP) proteins were resolved by SDS-PAGE and subjected to immunoblot analysis.…”

Section: Immunoprecipitation Studiesmentioning

confidence: 99%

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LIMK1/TPPP1/HDAC6 Is a Dual Actin and Microtubule Regulatory Complex That Promotes Drug Resistance

Schofield¹,

Gamell²,

Bernard³

2014

ABB

Self Cite

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In this study, we identified a novel protein complex consisting of LIM-Kinase 1 (LIMK1), Histone deacetylase 6 (HDAC6) and Tubulin Polymerization Promoting Protein 1 (TPPP1). Under basal conditions, assembly of the LIMK1/TPPP1/HDAC6 complex results in both inhibition of HDAC6 activity and LIMK1 activation. This leads to increased microtubule (MT) acetylation, a MT stabilizing modification, and actin filament (F-actin) destabilization. In response to activation of the Rhokinase (ROCK) signaling pathway, downstream phosphorylation of LIMK1 and TPPP1 leads to the dissociation of the LIMK1/TPPP1/HDAC6 complex. In turn, HDAC6 and LIMK1 activities are increased, which results in MT destabilization and F-actin stabilization. Finally, we reveal that increasing tubulin acetylation reduces the efficacy of chemotherapeutic drugs, suggesting that strategies to reduce acetyl-tubulin levels may be a viable option in treating drug-resistant tumors.

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Design and Rationale of the LAPLACE‐TIMI 57 Trial: A Phase II, Double‐Blind, Placebo‐Controlled Study of the Efficacy and Tolerability of a Monoclonal Antibody Inhibitor of PCSK9 in Subjects With Hypercholesterolemia on Background Statin Therapy

Kohli

Desai

Giugliano

et al. 2012

Clinical Cardiology

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Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone for the prevention of atherosclerotic heart disease, improving clinical outcomes and reducing vascular mortality in patients with hypercholesterolemia. The clinical benefits of LDL-C reduction appear to extend even to patients starting with LDL-C as low as 60–80 mg/dL prior to initiating therapy. Statins are the first-line agents for treating hypercholesterolemia and are effective in reducing LDL-C, but many patients are unable to achieve their optimal lipid targets despite intensive statin therapy. Therefore, there has been a strong impetus for the development of novel pharmacologic agents designed to lower LDL-C further in patients already on statin therapy. Genetic mutations resulting in altered cholesterol homeostasis provide valuable information regarding novel approaches for treating hypercholesterolemia. To that end, mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) were linked to altered levels of LDL-C, illustrating this protein’s role in lipid metabolism. PCSK9 promotes degradation of the LDL receptor, preventing its transport back to the cell surface and thereby increasing circulating LDL-C. Conversely, inhibition of PCSK9 can profoundly decrease circulating LDL-C, and thus is an attractive new target for LDL-C–lowering therapy. AMG 145 is a fully human monoclonal immunoglobulin G2 antibody that binds specifically to human PCSK9 and inhibits its interaction with the low-density lipoprotein receptor. In this manuscript, we describe the rationale and design of LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy–Thrombolysis In Myocardial Infarction 57 (LAPLACE-TIMI 57; NCT01380730), a 12-week, randomized, double-blind, dose-ranging, placebo-controlled study designed to assess the safety and efficacy of AMG 145 when added to statin therapy in patients with hypercholesterolemia.

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LIM kinase 1, a key regulator of actin dynamics, is widely expressed in embryonic and adult tissues

Cited by 88 publications

References 43 publications

Phosphorylation of Actin-Depolymerizing Factor/Cofilin by LIM-Kinase Mediates Amyloid -Induced Degeneration: A Potential Mechanism of Neuronal Dystrophy in Alzheimer's Disease

Phosphorylation of Actin-Depolymerizing Factor/Cofilin by LIM-Kinase Mediates Amyloid -Induced Degeneration: A Potential Mechanism of Neuronal Dystrophy in Alzheimer's Disease

LIMK1/TPPP1/HDAC6 Is a Dual Actin and Microtubule Regulatory Complex That Promotes Drug Resistance

Design and Rationale of the LAPLACE‐TIMI 57 Trial: A Phase II, Double‐Blind, Placebo‐Controlled Study of the Efficacy and Tolerability of a Monoclonal Antibody Inhibitor of PCSK9 in Subjects With Hypercholesterolemia on Background Statin Therapy

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