Cleavage and activation of LIM kinase 1 as a novel mechanism for calpain 2-mediated regulation of nuclear dynamics

AbstractCalpain-2 (CAPN2) is a processing enzyme ubiquitously expressed in mammalian tissues whose pleiotropic functions depend on the role played by its cleaved-products. Nuclear interaction networks, crucial for a number of molecular processes, could be modified by CAPN2 activity. However, CAPN2 functions in cell nucleus are poorly understood. To unveil CAPN2 functions in this compartment, the result of CAPN2-mediated interactions in cell nuclei was studied in breast cancer cell (BCC) lines. CAPN2 abundance was found to be determinant for its nucleolar localization during interphase. Those CAPN2-dependent components of nucleolar proteome, including the actin-severing protein cofilin-1 (CFL1), were identified by proteomic approaches. CAPN2 binding, cleavage and activation of LIM Kinase-1 (LIMK1), followed by CFL1 phosphorylation was studied. Upon CAPN2-depletion, full-length LIMK1 levels increased and CFL1/LIMK1 binding was inhibited. In addition, LIMK1 accumulated at the cell periphery and perinucleolar region and, the mitosis-specific increase of CFL1 phosphorylation and localization was altered, leading to aberrant mitosis and cell multinucleation. These findings uncover a mechanism for the role of CAPN2 during mitosis, unveil the critical role of CAPN2 in the interactions among nuclear components and, identifying LIMK1 as a new CAPN2-target, provide a novel mechanism for LIMK1 activation. CFL1 is crucial for cytoskeleton remodeling and mitosis, but also for the maintenance of nuclear structure, the movement of chromosomes and the modulation of transcription frequently altered in cancer cells. Consequently, the role of CAPN2 in the nuclear compartment might be extended to other actin-associated biological and pathological processes.

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28 THE REGULATION OF NEURONAL OUTGROWTH AND RETRACTION BY SEROTONIN RECEPTORS 5-HT4a AND 5-HT7: THE ROLE OF LIM KINASE 1.

Journal of Investigative Medicine ◽

10.2310/6650.2005.x0015.27 ◽

2006 ◽

Vol 54 (2) ◽

pp. S348.2-S348

Author(s):

A. Krbanjevic ◽

G. Liu ◽

J. Profirovic ◽

T. Voyno-Yasenetskaya

Keyword(s):

Serotonin Receptors ◽

Lim Kinase ◽

Lim Kinase 1 ◽

Neuronal Outgrowth

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Thrombin selectively engages LIM kinase 1 and slingshot-1L phosphatase to regulate NF-κB activation and endothelial cell inflammation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00071.2013 ◽

2013 ◽

Vol 305 (9) ◽

pp. L651-L664 ◽

Cited By ~ 14

Author(s):

Antony Leonard ◽

Catherine Marando ◽

Arshad Rahman ◽

Fabeha Fazal

Keyword(s):

Endothelial Cell ◽

Target Genes ◽

Nuclear Translocation ◽

Severe Form ◽

Actin Binding ◽

Critical Event ◽

Lim Kinase ◽

Lim Kinase 1 ◽

Proinflammatory Gene

Endothelial cell (EC) inflammation is a central event in the pathogenesis of many pulmonary diseases such as acute lung injury and its more severe form acute respiratory distress syndrome. Alterations in actin cytoskeleton are shown to be crucial for NF-κB regulation and EC inflammation. Previously, we have described a role of actin binding protein cofilin in mediating cytoskeletal alterations essential for NF-κB activation and EC inflammation. The present study describes a dynamic mechanism in which LIM kinase 1 (LIMK1), a cofilin kinase, and slingshot-1Long (SSH-1L), a cofilin phosphatase, are engaged by procoagulant and proinflammatory mediator thrombin to regulate these responses. Our data show that knockdown of LIMK1 destabilizes whereas knockdown of SSH-1L stabilizes the actin filaments through modulation of cofilin phosphorylation; however, in either case thrombin-induced NF-κB activity and expression of its target genes (ICAM-1 and VCAM-1) is inhibited. Further mechanistic analyses reveal that knockdown of LIMK1 or SSH-1L each attenuates nuclear translocation and thereby DNA binding of RelA/p65. In addition, LIMK1 or SSH-1L depletion inhibited RelA/p65 phosphorylation at Ser536, a critical event conferring transcriptional competency to the bound NF-κB. However, unlike SSH-1L, LIMK1 knockdown also impairs the release of RelA/p65 by blocking IKKβ-dependent phosphorylation/degradation of IκBα. Interestingly, LIMK1 or SSH-1L depletion failed to inhibit TNF-α-induced RelA/p65 nuclear translocation and proinflammatory gene expression. Thus this study provides evidence for a novel role of LIMK1 and SSH-1L in selectively regulating EC inflammation associated with intravascular coagulation.

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An Update on the Role of Ubiquitination in Melanoma Development and Therapies

Journal of Clinical Medicine ◽

10.3390/jcm10051133 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1133

Author(s):

Frédéric Soysouvanh ◽

Serena Giuliano ◽

Nadia Habel ◽

Najla El-Hachem ◽

Céline Pisibon ◽

...

Keyword(s):

Patient Outcomes ◽

Critical Role ◽

Therapeutic Strategies ◽

Biological Processes ◽

Large Array ◽

Skin Cancers ◽

Melanoma Patients ◽

Ubiquitination System ◽

Pleiotropic Functions

The ubiquitination system plays a critical role in regulation of large array of biological processes and its alteration has been involved in the pathogenesis of cancers, among them cutaneous melanoma, which is responsible for the most deaths from skin cancers. Over the last decades, targeted therapies and immunotherapies became the standard therapeutic strategies for advanced melanomas. However, despite these breakthroughs, the prognosis of metastatic melanoma patients remains unoptimistic, mainly due to intrinsic or acquired resistances. Many avenues of research have been investigated to find new therapeutic targets for improving patient outcomes. Because of the pleiotropic functions of ubiquitination, and because each step of ubiquitination is amenable to pharmacological targeting, much attention has been paid to the role of this process in melanoma development and resistance to therapies. In this review, we summarize the latest data on ubiquitination and discuss the possible impacts on melanoma treatments.

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Critical role of interferons in gastrointestinal injury repair

Nature Communications ◽

10.1038/s41467-021-22928-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Constance McElrath ◽

Vanessa Espinosa ◽

Jian-Da Lin ◽

Jianya Peng ◽

Raghavendra Sridhar ◽

...

Keyword(s):

Critical Role ◽

Mucosal Healing ◽

Type I ◽

Acute Colitis ◽

Colonic Injury ◽

Epithelial Regeneration ◽

Complex Interactions ◽

Pleiotropic Functions ◽

Deficient Mice

AbstractThe etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.

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Abstract 420: Critical role of MMP-2 and GATA-1 nuclear interaction in the regulation of ionizing radiation (IR)-induced IL-10/Stat3-mediated invasion and migration in glioblastoma.

10.1158/1538-7445.am2013-420 ◽

2013 ◽

Author(s):

Divya Kesanakurti ◽

Dilip Maddirela ◽

Meena Gujrati ◽

Jasti S. Rao

Keyword(s):

Ionizing Radiation ◽

Critical Role ◽

Nuclear Interaction ◽

Invasion And Migration ◽

And Migration

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LIM Kinase 1 Mediates Estradiol Effects on the Phosphorylation of Cofilin1 in Eutopic Endometrial Stromal Cells During the Invasion and Proliferation of Endometriosis

Reproductive Sciences ◽

10.1177/1933719119828076 ◽

2019 ◽

Vol 26 (11) ◽

pp. 1499-1505 ◽

Cited By ~ 3

Author(s):

Jing Liu ◽

Zhifang Zhang ◽

Jiamei Liu ◽

Danbo Wang

Keyword(s):

Rna Interference ◽

Cell Invasion ◽

Stromal Cells ◽

Endometrial Stromal Cells ◽

Lim Kinase ◽

Endometrial Cells ◽

Lim Kinase 1 ◽

Gynecological Disease ◽

Cell Invasiveness

Endometriosis is an estrogen-dependent gynecological disease; however, the mechanism by which estradiol promotes the development of endometriosis, including invasion and proliferation, remains unclear. Estradiol is involved in cell invasion and proliferation by regulating the cytoskeleton. The abnormally high expression of cytoskeletal regulators (LIM kinase 1 [LIMK1] and cofilin1) is closely related to increased invasiveness and proliferation of eutopic endometrial stromal cells from endometriosis patients compared to normal eutopic endometrial cells. The aim of this study was to analyze the role of estradiol during invasion and proliferation through the LIMK1/cofilin1 pathway in the endometrium of women with endometriosis. To address this, primary eutopic endometrial stromal cells were isolated from the uteri of patients with endometriosis and cultured without estradiol. The phosphorylation of cofilin1 was analyzed by western blotting. Cell invasiveness and proliferation were evaluated following LIMK1 knockdown by RNA interference technology. We found that, before LIMK1silencing, the phosphorylation levels of cofilin1 and LIMK1 of eutopic endometrial stromal cells from endometriosis patients treated with estradiol were higher than cells not treated with estradiol ( P < .05 and P < .01, respectively). The total levels of cofilin1 and LIMK1 protein did not change ( P > .05 and P > .05, respectively). After LIMK1 silencing, the phosphorylation of cofilin1 by estradiol was significantly reduced, and invasiveness and proliferation were clearly and concurrently decreased ( P < .05 and P < .05, respectively). Thus, the phosphorylation of cofilin1 by estradiol is mediated by LIMK1, and estradiol is involved in regulating cell invasion and proliferation in endometriotic patients through the LIMK1/cofilin1 pathway.

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A role of LIM kinase 1/cofilin pathway in regulating endocytic trafficking of EGF receptor in human breast cancer cells

Histochemistry and Cell Biology ◽

10.1007/s00418-006-0198-x ◽

2006 ◽

Vol 126 (5) ◽

pp. 627-638 ◽

Cited By ~ 24

Author(s):

Yukio Nishimura ◽

Kiyoko Yoshioka ◽

Ora Bernard ◽

Biborka Bereczky ◽

Kazuyuki Itoh

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Egf Receptor ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Lim Kinase ◽

Lim Kinase 1

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The Role of the SLP in Autism Spectrum Disorder Screening and Assessment

Perspectives on Language Learning and Education ◽

10.1044/lle15.2.50 ◽

2008 ◽

Vol 15 (2) ◽

pp. 50-59 ◽

Cited By ~ 1

Author(s):

Amy Philofsky

Keyword(s):

Language Development ◽

Critical Role ◽

Children With Autism ◽

Autism Spectrum ◽

Children With Asd ◽

Prevalence Estimates ◽

Notable Increase ◽

Screening Assessment ◽

Critical Components

AbstractRecent prevalence estimates for autism have been alarming as a function of the notable increase. Speech-language pathologists play a critical role in screening, assessment and intervention for children with autism. This article reviews signs that may be indicative of autism at different stages of language development, and discusses the importance of several psychometric properties—sensitivity and specificity—in utilizing screening measures for children with autism. Critical components of assessment for children with autism are reviewed. This article concludes with examples of intervention targets for children with ASD at various levels of language development.

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