LIM kinase-1 (LIMK1) and LIM kinase-2 (LIMK2) are actin-binding kinases that phosphorylate members of the ADF/cofilin family of actin binding and filament severing proteins. ADF/cofilin are the only substrates yet identified for the LIM kinases. LIM kinases directly phosphorylate and inactivate members of the cofilin family, resulting in stabilization of filamentous (F)-actin. Lim kinases are activated by signaling through small GTPases of the Rho family. Upstream, LIMK1 is regulated by Pak1, and LIMK2 by the Rho-dependent kinase ROCK. Lim Kinases are activated by PAK (p21-activated kinase).
An overview of LIMK
LIM kinase (LIMK) is a protein kinase composed of Ser/Thr. Although identified as Ser/Thr kinases, LIMK is also classified as tyrosine kinase-like proteins due to the primary sequences. The major function of LIMK is to phosphorylate the Ser3 residue of three different substrates: non-muscle cofilin, muscle cofilin, and actin depolymerizing. After phosphorylated, LIMK fails to bind to actin and severely affects its filaments, which accumulates actin polymers and leads to dysregulation of actin-mediated cytoskeletal changes. These biological processes are able to regulate lots of cellular functions, such as differentiation, spreading, apoptosis and so on.
Major types of LIMK
There are only two members in the LIMK family: LIMK1 and LIMK2. In the 1990s, the two kinases were discovered and they have high similarity in the aspect of amino acid sequence. Both of them consist of three structural domains: two LIM domains and a PDZ domain. LIMK1 and LIMK2 are involved in regulating a series of biological behaviors of tumor cells, including migration and proliferation. Although LIMK1 and LIMK2 are similar in chemical structure, their positions in cells are completely different. LIKM1 is mainly attached to the mucous plaque in the cytoplasm, while LIMK2 is concentrated in the common spots in the cytoplasm and widely expressed in various tissues in the body.
Inhibition of LIMK
Bristol-Myers Squibb reported the first class of LIMK inhibitors, such as BMS-3 and BMS-3 that could inhibit both of LIMK1 and LIMK2. In 2009, researchers from Lexicon discoveredabout 40 compounds that have the ability to inhibit LIMK-2 dependent cofilin phosphorylation. Experiments have revealed that the LIMK inhibitor R10015 exerted its function by binding to ATP-binding proteins, disturbing the synthesis, nuclear migration and release of virus particles, indicating that LIMK inhibitors, like staurosporine and dabrafenib, may be used as a new kind of broad spectrum antiviral drugs.
LIMK and diseases
LIMK is mainly involved in the invasion and migration processes of tumor cells, and its phosphorylation causes dynamic changes of cytoskeletal actin and depolymerization of actin. It is highly expressed in many malignant tumor tissues, such as prostate cancer, breast cancer, lung cancer, malignant glioma cells. It is also reported that LIMK is related to nervous system diseases and other diseases like glaucoma.
1. Manetti, F. LIM kinases are attractive targets with many macromolecular partners and only a few small molecule regulators. Medicinal Research Reviews 32, 968-998 (2012).
2. Bernard, O. Lim kinases, regulators of actin dynamics. Int J Biochem Cell Biol 39, 1071-1076 (2007).
3. Manetti, F. Recent advances in the rational design and development of LIM kinase inhibitors are not enough to enter clinical trials. (2018).