Rho-associated Coiled-coil Kinase (ROCK) Protein Controls Microtubule Dynamics in a Novel Signaling Pathway That Regulates Cell Migration

Schofield, Alice; Steel, Rohan; Bernard, Ora

doi:10.1074/jbc.m112.394965

Cited by 71 publications

(89 citation statements)

References 38 publications

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“…Overexpression of TPPP1 in cells promotes MT polymerization and an increase in MT acetylation, whereas introduction of TPPP1 RNAi reduces MT acetylation [43]. Phosphorylation of TPPP1 by Rho-associated coiled-coil kinase (ROCK) and cyclin-dependent kinase 1 (CDK1) impairs the interaction between TPPP1 and HDAC6, which, in turn, results in increased HDAC6 activity followed by a decrease in cell motility and an increase in cell proliferation, respectively [46,47]. Moreover, a broad spectrum of regulators, which directly interact with and inhibit HDAC6 tubulin deacetylase activity or aggresome formation ability, has been well documented, including paxillin [48], CYLD [49,50], dysferlin [51], Mdp3 [52], p62 [53] and RanBPM [54].…”

Section: Sam68mentioning

confidence: 99%

Cellular defence or viral assist: the dilemma of HDAC6

Zheng

Jiang

et al. 2017

Journal of General Virology

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Histone deacetylase 6 (HDAC6) is a unique cytoplasmic deacetylase that regulates various important biological processes by preventing protein aggregation and deacetylating different non-histone substrates including tubulin, heat shock protein 90, cortactin, retinoic acid inducible gene I and b-catenin. Growing evidence has indicated a dual role for HDAC6 in viral infection and pathogenesis: HDAC6 may represent a host defence mechanism against viral infection by modulating microtubule acetylation, triggering antiviral immune response and stimulating protective autophagy, or it may be hijacked by the virus to enhance proinflammatory response. In this review, we will highlight current data illustrating the complexity and importance of HDAC6 in viral pathogenesis. We will summarize the structure and functional specificity of HDAC6, and its deacetylaseand ubiquitin-dependent activity in key cellular events in response to virus infection. We will also discuss how HDAC6 exerts its direct or indirect histone modification ability in viral lytic-latency switch.

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Section: Sam68mentioning

confidence: 99%

Cellular defence or viral assist: the dilemma of HDAC6

Zheng

Jiang

et al. 2017

Journal of General Virology

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“…LIMKs are activated through phosphorylation by Rho-associated coiled-coil kinase (ROCK), p21-activated ki-nase 1 (PAK1) and PAK4, downstream effectors of the small GTPases Rho, Rac and Cdc42, respectively [3]- [5]. Interestingly, although it has been reported that LIMK1 and LIMK2 interact with Tubulin Polymerization Promoting Protein 1 (TPPP1) in vitro and in vivo [6]- [8], TPPP1 is not a LIMK substrate in cells [9].…”

Section: Introductionmentioning

confidence: 99%

“…Flag-LIMK1, Flag-LIMK1-DN, Flag-HADC6, myc-cofilin, myc-cofilin S3A, myc-cofilin S3D constructs were transiently transfected into U2OS cells using the Lipofectamine™ 2000 (Life Technologies) transfection reagent according to manufacturer's recommendations. Cells expressing Flag-TPPP1 were generated as previously described [9].…”

Section: Mammalian Cell Culturementioning

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

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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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“…MT dynamics is spatially and temporally regulated by several pathways and MT-interacting proteins (see Table 1): tau, a MT-associated protein (MAP) that stabilizes MTs [Maccioni and Cambiazo, 1995], and katanin, the MT-severing enzyme [Roll-Mecak and McNally, 2010], both interact with the MT lattice; PAR-1 (also known as MARK) phosphorylates classical MAPs and detaches MAPs from MTs [Matenia and Mandelkow, 2009]; +TIPs, the MT plusend-tracking proteins, specifically control the dynamic properties of the MT end [Gouveia and Akhmanova, 2010;Schuyler and Pellman, 2001]; ROCK pathway regulates MT dynamics via phosphorylation of the tubulin polymerization promoting protein 1 (TPPP1/p25) [Schofield et al 2012]; (aPKC)-Aurora A-NDEL1 pathway is crucial for the regulation of MT organization during neurite extension [Mori et al 2009]; Dishevelled (Dvl) pathway and the cooperation of Wnt-Dvl pathways increase MT stability though Gsk3β inhibition and c-Jun N-terminal kinase (JNK) activation [Ciani and Salinas, 2007]. These are only some of the known regulatory mechanisms that contribute to orchestrate MT dynamic remodelling.…”

Section: Microtubule Dynamics Regulationmentioning

confidence: 99%

Notch signalling in adult neurons: a potential target for microtubule stabilization

Bonini

Ferrari-Toninelli

Montinaro

et al. 2013

Ther Adv Neurol Disord

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Cytoskeletal dysfunction has been proposed during the last decade as one of the main mechanisms involved in the aetiology of several neurodegenerative diseases. Microtubules are basic elements of the cytoskeleton and the dysregulation of microtubule stability has been demonstrated to be causative for axonal transport impairment, synaptic contact degeneration, impaired neuronal function leading finally to neuronal loss. Several pathways are implicated in the microtubule assembly/disassembly process. Emerging evidence is focusing on Notch as a microtubule dynamics regulator. We demonstrated that activation of Notch signalling results in increased microtubule stability and changes in axonal morphology and branching. By contrast, Notch inhibition leads to an increase in cytoskeleton plasticity with intense neurite remodelling. Until now, several microtubule-binding compounds have been tested and the results have provided proof of concept that microtubule-binding agents or compounds with the ability to stabilize microtubules may have therapeutic potential for the treatment of Alzheimer's disease and other neurodegenerative diseases. In this review, based on its key role in cytoskeletal dynamics modulation, we propose Notch as a new potential target for microtubule stabilization.

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Rho-associated Coiled-coil Kinase (ROCK) Protein Controls Microtubule Dynamics in a Novel Signaling Pathway That Regulates Cell Migration

Cited by 71 publications

References 38 publications

Cellular defence or viral assist: the dilemma of HDAC6

Cellular defence or viral assist: the dilemma of HDAC6

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

Notch signalling in adult neurons: a potential target for microtubule stabilization

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