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LIM Kinases: From Molecular to Pathological Features

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 20526

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Special Issue Editors

Dr. Hélène Bénédetti

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Guest Editor

Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique, Orleans, France
Interests: cell signaling; LIM kinases; neurofibromatosis type I; cytoskeleton remodeling; post-translational modifications (SUMO)

Dr. Béatrice Vallée-Méheust

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Guest Editor

Special Issue Information

Dear Colleagues,

The LIM kinases LIMK1 and LIMK2 were discovered in 1994 and 1995, respectively. They were characterized as dual kinases phosphorylating both Ser/Thr and Tyr residues. Their role in actin cytoskeleton remodeling was quickly demonstrated via the inhibition of their substrate actin depolymerizing factor ADF/cofilin. They also regulate microtubule polymerization, but the molecular actors in this process remain unknown. According to their role in cytoskeleton remodeling, LIM kinases contribute to many cellular functions, such as cell motility, morphogenesis, division, differentiation, apoptosis, neuronal morphology, neuritogenesis, and oncogenesis. Recently, the number of LIM kinase substrates has started to grow, suggesting other functions for these proteins. In the last 10 years, LIM kinases have also attracted special attention as their involvement in several diseases has been shown.

In this Special Issue, we want to provide an extensive overview of these very peculiar kinases, starting from their molecular characterization and ending with their pathological implications. A first set of reviews will describe their three-dimensional structure and their non-conventional interaction with their well-characterized substrate cofilin. A second set of reviews will focus on their different, less-known substrates, on their regulators, and on the different cell signaling pathways they are part of. A third set of reviews will focus on the different diseases in which LIM kinases are involved and for which they constitute emerging therapeutic targets: cancer, neurological diseases, viral infection, and reproduction defects. Finally, a fourth set reviews will update the different strategies for inhibiting these kinases: small chemical molecules, miR.

Dr. Hélène Bénédetti
Dr. Béatrice Vallée-Méheust
Guest Editors

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Keywords

LIM kinases
cytoskeleton
cofilin
cell signaling pathways
cancer
neurological defects
kinase inhibitors

Published Papers (7 papers)

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Editorial

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3 pages, 213 KiB

Open AccessEditorial

LIM Kinases: From Molecular to Pathological Features

by Hélène Bénédetti and Béatrice Vallée

Cells 2023, 12(12), 1649; https://doi.org/10.3390/cells12121649 - 16 Jun 2023

Viewed by 797

Abstract

LIM kinases (LIMKs), LIMK1 and LIMK2, are atypical kinases, as they are the only two members of the LIM kinase family harbouring two LIM domains at their N-terminus and a kinase domain at their C-terminus [...] Full article

(This article belongs to the Special Issue LIM Kinases: From Molecular to Pathological Features)

Review

Jump to: Editorial

40 pages, 4215 KiB

Open AccessReview

LIM Kinases, LIMK1 and LIMK2, Are Crucial Node Actors of the Cell Fate: Molecular to Pathological Features

by Elodie Villalonga, Christine Mosrin, Thierry Normand, Caroline Girardin, Amandine Serrano, Bojan Žunar, Michel Doudeau, Fabienne Godin, Hélène Bénédetti and Béatrice Vallée

Cells 2023, 12(5), 805; https://doi.org/10.3390/cells12050805 - 4 Mar 2023

Cited by 8 | Viewed by 4146

Abstract

LIM kinase 1 (LIMK1) and LIM kinase 2 (LIMK2) are serine/threonine and tyrosine kinases and the only two members of the LIM kinase family. They play a crucial role in the regulation of cytoskeleton dynamics by controlling actin filaments and microtubule turnover, especially through the phosphorylation of cofilin, an actin depolymerising factor. Thus, they are involved in many biological processes, such as cell cycle, cell migration, and neuronal differentiation. Consequently, they are also part of numerous pathological mechanisms, especially in cancer, where their involvement has been reported for a few years and has led to the development of a wide range of inhibitors. LIMK1 and LIMK2 are known to be part of the Rho family GTPase signal transduction pathways, but many more partners have been discovered over the decades, and both LIMKs are suspected to be part of an extended and various range of regulation pathways. In this review, we propose to consider the different molecular mechanisms involving LIM kinases and their associated signalling pathways, and to offer a better understanding of their variety of actions within the physiology and physiopathology of the cell. Full article

(This article belongs to the Special Issue LIM Kinases: From Molecular to Pathological Features)

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Graphical abstract

22 pages, 2542 KiB

Open AccessReview

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo

by Rayan Berabez, Sylvain Routier, Hélène Bénédetti, Karen Plé and Béatrice Vallée

Cells 2022, 11(13), 2090; https://doi.org/10.3390/cells11132090 - 30 Jun 2022

Cited by 9 | Viewed by 2494

Abstract

LIM Kinases are important actors in the regulation of cytoskeleton dynamics by controlling microtubule and actin filament turnover. The signaling pathways involving LIM kinases for actin filament remodeling are well established. They are downstream effectors of small G proteins of the Rho-GTPases family and have become promising targets for the treatment of several major diseases because of their position at the lower end of these signaling cascades. Cofilin, which depolymerizes actin filaments, is the best-known substrate of these enzymes. The phosphorylation of cofilin to its inactive form by LIM kinases avoids actin filament depolymerization. The balance between phosphorylated and non-phosphorylated cofilin is thought to play an important role in tumor cell invasion and metastasis. Since 2006, many small molecules have been developed for LIMK inhibition, and in this review article, we will discuss the structure–activity relationships of the few inhibitor families that have been tested in vivo on different pathological models. Full article

(This article belongs to the Special Issue LIM Kinases: From Molecular to Pathological Features)

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Graphical abstract

17 pages, 687 KiB

Open AccessFeature PaperReview

The Role of LIM Kinases during Development: A Lens to Get a Glimpse of Their Implication in Pathologies

by Anne-Sophie Ribba, Sandrine Fraboulet, Karin Sadoul and Laurence Lafanechère

Cells 2022, 11(3), 403; https://doi.org/10.3390/cells11030403 - 25 Jan 2022

Cited by 7 | Viewed by 3416

Abstract

The organization of cell populations within animal tissues is essential for the morphogenesis of organs during development. Cells recognize three-dimensional positions with respect to the whole organism and regulate their cell shape, motility, migration, polarization, growth, differentiation, gene expression and cell death according to extracellular signals. Remodeling of the actin filaments is essential to achieve these cell morphological changes. Cofilin is an important binding protein for these filaments; it increases their elasticity in terms of flexion and torsion and also severs them. The activity of cofilin is spatiotemporally inhibited via phosphorylation by the LIM domain kinases 1 and 2 (LIMK1 and LIMK2). Phylogenetic analysis indicates that the phospho-regulation of cofilin has evolved as a mechanism controlling the reorganization of the actin cytoskeleton during complex multicellular processes, such as those that occur during embryogenesis. In this context, the main objective of this review is to provide an update of the respective role of each of the LIM kinases during embryonic development. Full article

(This article belongs to the Special Issue LIM Kinases: From Molecular to Pathological Features)

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Figure 1

12 pages, 3024 KiB

Open AccessReview

Structural Aspects of LIMK Regulation and Pharmacology

by Deep Chatterjee, Franziska Preuss, Verena Dederer, Stefan Knapp and Sebastian Mathea

Cells 2022, 11(1), 142; https://doi.org/10.3390/cells11010142 - 2 Jan 2022

Cited by 12 | Viewed by 3104

Abstract

Malfunction of the actin cytoskeleton is linked to numerous human diseases including neurological disorders and cancer. LIMK1 (LIM domain kinase 1) and its paralogue LIMK2 are two closely related kinases that control actin cytoskeleton dynamics. Consequently, they are potential therapeutic targets for the treatment of such diseases. In the present review, we describe the LIMK conformational space and its dependence on ligand binding. Furthermore, we explain the unique catalytic mechanism of the kinase, shedding light on substrate recognition and how LIMK activity is regulated. The structural features are evaluated for implications on the drug discovery process. Finally, potential future directions for targeting LIMKs pharmacologically, also beyond just inhibiting the kinase domain, are discussed. Full article

(This article belongs to the Special Issue LIM Kinases: From Molecular to Pathological Features)

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Graphical abstract

9 pages, 998 KiB

Open AccessReview

The Role of LIM Kinase in the Male Urogenital System

by Juhyun Park, Soo Woong Kim and Min Chul Cho

Cells 2022, 11(1), 78; https://doi.org/10.3390/cells11010078 - 28 Dec 2021

Cited by 10 | Viewed by 2464

Abstract

The LIM kinases (LIMK1 and LIMK2), known as downstream effectors, and the Rho-associated protein kinase (ROCK), a regulator of actin dynamics, have effects on a diverse set of cellular functions. The LIM kinases are involved in the function of the male urogenital system by smooth muscle contraction via phosphorylation of cofilin and subsequent actin cytoskeleton reorganization. Although LIMK1 and LIMK2 share sequence similarities as serine protein kinases, different tissue distribution patterns and distinct localization during cell cycle progression suggest other biological functions for each kinase. During meiosis and mitosis, the LIMK1/2–cofilin signaling facilitates the orchestrated chromatin remodeling between gametogenesis and the actin cytoskeleton. A splicing variant of the LIMK2 transcript was expressed only in the testis. Moreover, positive signals with LIMK2-specific antibodies were detected mainly in the nucleus of the differentiated stages of germ cells, such as spermatocytes and early round spermatids. LIMK2 plays a vital role in proper spermatogenesis, such as meiotic processes of spermatogenesis after puberty. On the other hand, the literature evidence revealed that a reduction in LIMK1 expression enhanced the inhibitory effects of a ROCK inhibitor on the smooth muscle contraction of the human prostate. LIMK1 may have a role in urethral obstruction and bladder outlet obstruction in men with benign prostatic hyperplasia. Moreover, LIMK1 expression was reduced in urethral stricture. The reduced LIMK1 expression caused the impaired proliferation and migration of urethral fibroblasts. In addition, the activated LIMK2–cofilin pathway contributes to cavernosal fibrosis after cavernosal nerve injury. Recent evidence demonstrated that short-term inhibition of LIMK2 from the immediate post-injury period prevented cavernosal fibrosis and improved erectile function in a rat model of cavernosal nerve injury. Furthermore, chronic inhibition of the LIMK2–cofilin pathway significantly restrained the cavernosal veno-occlusive dysfunction, the primary pathophysiologic mechanism of post-prostatectomy erectile dysfunction through suppressing fibrosis in the corpus cavernosum. In conclusion, the LIM kinases–cofilin pathway appears to play a role in the function of the male urogenital system through actin cytoskeleton reorganization and contributes to the pathogenesis of several urogenital diseases. Therefore, LIM kinases may be a potential treatment target in urogenital disorder. Full article

(This article belongs to the Special Issue LIM Kinases: From Molecular to Pathological Features)

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Graphical abstract

16 pages, 1590 KiB

Open AccessReview

LIM Kinases in Osteosarcoma Development

by Régis Brion, Laura Regnier, Mathilde Mullard, Jérome Amiaud, Françoise Rédini and Franck Verrecchia

Cells 2021, 10(12), 3542; https://doi.org/10.3390/cells10123542 - 15 Dec 2021

Cited by 7 | Viewed by 3315

Abstract

Tumorigenesis is a long-term and multistage process that often leads to the formation of metastases. During this pathological course, two major events appear to be crucial: primary tumour growth and metastatic expansion. In this context, despite research and clinical advances during the past decades, bone cancers remain a leading cause of death worldwide among paediatric cancer patients. Osteosarcomas are the most common malignant bone tumours in children and adolescents. Notwithstanding advances in therapeutic treatments, many patients succumb to these diseases. In particular, less than 30% of patients who demonstrate metastases at diagnosis or are poor responders to chemotherapy survive 5 years after initial diagnosis. LIM kinases (LIMKs), comprising LIMK1 and LIMK2, are common downstream effectors of several signalization pathways, and function as a signalling node that controls cytoskeleton dynamics through the phosphorylation of the cofilin family proteins. In recent decades, several reports have indicated that the functions of LIMKs are mainly implicated in the regulation of actin microfilament and the control of microtubule dynamics. Previous studies have thus identified LIMKs as cancer-promoting regulators in multiple organ cancers, such as breast cancer or prostate cancer. This review updates the current understanding of LIMK involvement in osteosarcoma progression. Full article

(This article belongs to the Special Issue LIM Kinases: From Molecular to Pathological Features)

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