☆ 4.8 Article

LIM domain kinases as potential therapeutic targets for neurofibromatosis type 2

ONCOGENE (2014)

期刊

ONCOGENE

卷 33, 期 27, 页码 3571-3582

出版社

NATURE PUBLISHING GROUP

DOI: 10.1038/onc.2013.320

关键词

LIMK; cell proliferation; Neurofibromatosis; schwannomas; cytoskeleton dynamics; cell cycle

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Biochemistry & Molecular Biology Oncology Cell Biology Genetics & Heredity

资金

DHHS/NIH [5R01DC10189]
Children's Tumor Foundation

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摘要

Neurofibromatosis type 2 (NF2) is caused by mutations in the NF2 gene that encodes a tumor-suppressor protein called merlin. NF2 is characterized by formation of multiple schwannomas, meningiomas and ependymomas. Merlin loss-of-function is associated with increased activity of Rac and p21-activated kinases (PAKs) and deregulation of cytoskeletal organization. LIM domain kinases (LIMK1 and 2) are substrate for Cdc42/Rac-PAK and modulate actin dynamics by phosphorylating cofilin at serine-3. This modification inactivates the actin severing and depolymerizing activity of cofilin. LIMKs also translocate into the nucleus and regulate cell cycle progression. Significantly, LIMKs are overexpressed in several tumor types, including skin, breast, lung, liver and prostate. Here we report that mouse Schwann cells (MSCs) in which merlin function is lost as a result of Nf2 exon2 deletion (Nf2(Delta Ex2)) exhibited increased levels of LIMK1, LIMK2 and active phospho-Thr508/505-LIMK1/2, as well as phospho-Ser3-cofilin, compared with wild-type normal MSCs. Similarly, levels of LIMK1 and 2 total protein and active phosphorylated forms were elevated in human vestibular schwannomas compared with normal human Schwann cells (SCs). Reintroduction of wild-type NF2 into Nf2(Delta Ex2) MSC reduced LIMK1 and LIMK2 levels. We show that pharmacological inhibition of LIMK with BMS-5 decreased the viability of Nf2(Delta Ex2) MSCs in a dose-dependent manner, but did not affect viability of control MSCs. Similarly, LIMK knockdown decreased viability of Nf2(Delta Ex2) MSCs. The decreased viability of Nf2(Delta Ex2) MSCs was not due to caspase-dependent or -independent apoptosis, but rather due to inhibition of cell cycle progression as evidenced by accumulation of cells in G(2)/M phase. Inhibition of LIMKs arrests cells in early mitosis by decreasing aurora A activation. Our results suggest that LIMKs are potential drug targets for NF2 and tumors associated with merlin deficiency.

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

Elodie Villalonga, Christine Mosrin, Thierry Normand, Caroline Girardin, Amandine Serrano, Bojan Zunar, Michel Doudeau, Fabienne Godin, Helene Benedetti, Beatrice Vallee

Summary: LIM kinase 1 (LIMK1) and LIM kinase 2 (LIMK2) are crucial regulators of cytoskeleton dynamics, particularly through phosphorylation of cofilin. They are involved in various biological processes, including cell cycle, cell migration, and neuronal differentiation. Their role in cancer and other pathological mechanisms has led to the development of inhibitors, and their interaction with signaling pathways extends beyond the Rho family GTPase pathway. This review explores the molecular mechanisms and physiological significance of LIM kinases in cell biology.

CELLS (2023)