Recent Findings Confirm LIM Domain Kinases as Emerging Target Candidates for Cancer Therapy

F.      Manetti

doi:10.2174/156800912800673266

Abstract

The two members of the LIM domain kinase family (LIMK1 and LIMK2) represent crucial keys in the signaling pathways that modulate the structure and activity of actin cytoskeleton. They maintain the optimal balance between phosphorylated and unphosphorylated cofilin that in turn acts by severing filamentous actin into globular actin and ensures actin turnover and cytoskeleton regulation. Many macromolecular partners able to regulate LIMK activity (positive and negative regulators) do exist. Proteins that enhance or reduce the nucleocytoplasmic shuttling of LIMK by direct or indirect interaction are also known. Among many LIMK activators, members of the Rho family of small GTPases (i.e., Rho, Rac, and Cdc42) and their downstream effectors (i.e., ROCK, PAK, and MK2) are involved in the progression of various human cancers toward invasive and metastatic stages. As LIMK are centrally positioned in the pathways leading to cytoskeleton dynamics and regulation, they could be considered as valuable targets for actin regulation. Fine modulation of LIMK activity could be a major challenge to inhibit tumor cell invasion mediated by one or a combination of the upstream signaling factors. As LIMK play a critical role in tumor cell invasion, they may be candidate targets for developing novel therapeutic agents toward tumor invasion and metastasis.

Keywords: Actin cytoskeletal dynamics, actin-depolymerizing factor, cofilin, cancer cells, LIM domain kinases, metastasis, small molecule LIMK inhibitors

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