LIM kinases (LIMKs), EC 184.108.40.206, are dual specificity kinases (serine/threonine and tyrosine), which phosphorylate and inactivate cofilin (a key regulator of actin cytoskeleton dynamics). There are two isoforms of LIMK: LIMK1 and LIMK2. LIMKs contain two N-terminal LIM motifs, a PDZ domain, and a C-terminal protein kinase domain.
LIMKs are regulated by the Rho-kinases ROCKI and ROCKII as well as the p21-activated kinases PAK1 and PAK4. Activated LIMKs regulate actin polymerization by phosphorylating cofilin which results in the stabilization of the filamentous actin polymer. This regulates cell cycle progression and cytoskeleton organization, as well as neuronal differentiation. In addition the formation of mature dendritic spines and synapses is in part driven by the ability of FAK to activate the RhoA-ROCK-LIMK1 pathway. Both isoforms of LIMK are ubiquitously expressed with the highest levels of LIMK1 found in the embryonic brain and the highest levels of LIMK2 found in the placenta, liver, lungs, pancreas and kidney. LIMK1 and LIMK2 have different roles in chromosome segregation and mitotic spindle organization and have distinctly different subcellular localizations, with LIMK1 restricted to focal adhesion sites and LIMK2 dispersed throughout the cytosol.
LIMK is highly expressed in many different types of tumors, with over expression of LIMK and the hyperphosphorylation of cofilin being implicated in the pathology of cancer cell invasion and metastasis. Futhermore inhibition of LIMK has been shown to stabilize microtubules and suppress cancer cell growth even in multidrug-resistant cancer cell lines and has thus been identified as a potential therapeutic target. LIMK1 has also been implicated as having a role in the pathogenesis of the neural development disorder Williams syndrome.
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Literature for LIMK
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