LIM kinases are attractive targets with many macromolecular partners and only a few small molecule regulators

Abstract

The LIM kinases 1 and 2 (LIMK1 and LIMK2) are dual specificity (serine/threonine and tyrosine) kinases. Although they show significant structural similarity, LIMK1 and LIMK2 show different expression, subcellular localization, and functions. They are involved in many cellular functions, such as migration, cycle, and neuronal differentiation and also have a role in pathological processes, such as cancer cell invasion and metastatis, as well as in neurodevelopmental disorders (namely, the William's syndrome). LIM kinases have a relevant number of known partners that are able to induce or limit the ability of LIMK1 and LIMK2 to phosphorylate and inactivate their major substrate, cofilin. On the contrary, only a limited number of small molecules that interact with the two proteins to modulate their kinase activity have been identified. In this review, the most important partners of LIM kinases and their modulating activity toward LIMKs are described. The small compounds identified as LIMK1 and LIMK2 modulators are also reported, as well as their role as possible therapeutic agents for LIMK-induced diseases.

Pharmacological Inhibition of LIM Kinase Stabilizes Microtubules and Inhibits Neoplastic Growth

“…Their effects can be observed in real time by live cell imaging. To date only 2 cell-permeable inhibitors of LIMK have been described with limited experimental data about their specificity (33,34,37,38). Moreover,…”

LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury

“…[25][26][27][28] Since rod axonal and neuritic plasticity requires morphologic change, actin filament rearrangement is presumably necessary. Thus LIMK activity is very likely to be involved in the response of photoreceptors to injury.…”

LIM Kinase Inhibitor Pyr1 Reduces the Growth and Metastatic Load of Breast Cancers

“…LIMK activity is mainly regulated by the Rho-GTPases (RhoA, Rac, and Cdc42) through their downstream kinases ROCK, PAK1, PAK4, and MRCK (1). The activation of the Rho-GTPases and their effectors, including LIMK, have been reported as playing important roles in tumor development and progression (8)(9)(10)(11)(12)(13). Expression of LIMK or cofilin phosphorylation is elevated in malignant melanoma (14), glioma (15), prostate (4,16,17), and breast tumors (18,19).…”