LIMK1

Official Full Name

LIM domain kinase 1

Organism

Homo sapiens

GeneID

3984

Background

There are approximately 40 known eukaryotic LIM proteins, so named for the LIM domains they contain. LIM domains are highly conserved cysteine-rich structures containing 2 zinc fingers. Although zinc fingers usually function by binding to DNA or RNA, the LIM motif probably mediates protein-protein interactions. LIM kinase-1 and LIM kinase-2 belong to a small subfamily with a unique combination of 2 N-terminal LIM motifs and a C-terminal protein kinase domain. LIMK1 is a serine/threonine kinase that regulates actin polymerization via phosphorylation and inactivation of the actin binding factor cofilin. This protein is ubiquitously expressed during development and plays a role in many cellular processes associated with cytoskeletal structure. This protein also stimulates axon growth and may play a role in brain development. LIMK1 hemizygosity is implicated in the impaired visuospatial constructive cognition of Williams syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Feb 2011]

Synonyms

LIMK; LIMK-1;

Bio Chemical Class

Kinase

Protein Sequence

MRLTLLCCTWREERMGEEGSELPVCASCGQRIYDGQYLQALNADWHADCFRCCDCSASLSHQYYEKDGQLFCKKDYWARYGESCHGCSEQITKGLVMVAGELKYHPECFICLTCGTFIGDGDTYTLVEHSKLYCGHCYYQTVVTPVIEQILPDSPGSHLPHTVTLVSIPASSHGKRGLSVSIDPPHGPPGCGTEHSHTVRVQGVDPGCMSPDVKNSIHVGDRILEINGTPIRNVPLDEIDLLIQETSRLLQLTLEHDPHDTLGHGLGPETSPLSSPAYTPSGEAGSSARQKPVLRSCSIDRSPGAGSLGSPASQRKDLGRSESLRVVCRPHRIFRPSDLIHGEVLGKGCFGQAIKVTHRETGEVMVMKELIRFDEETQRTFLKEVKVMRCLEHPNVLKFIGVLYKDKRLNFITEYIKGGTLRGIIKSMDSQYPWSQRVSFAKDIASGMAYLHSMNIIHRDLNSHNCLVRENKNVVVADFGLARLMVDEKTQPEGLRSLKKPDRKKRYTVVGNPYWMAPEMINGRSYDEKVDVFSFGIVLCEIIGRVNADPDYLPRTMDFGLNVRGFLDRYCPPNCPPSFFPITVRCCDLDPEKRPSFVKLEHWLETLRMHLAGHLPLGPQLEQLDRGFWETYRRGESGLPAHPEVPD

Open

Approved Drug

Clinical Trial Drug

Discontinued Drug

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Detailed Information

LIM domain kinase 1 (LIMK1) is a serine/threonine and tyrosine dual-specificity kinase, characterized by the presence of LIM and PDZ protein-protein interaction domains. It plays a pivotal role in regulating cytoskeletal dynamics, particularly through modulating the actin filament system. Since its discovery in 1994 by the teams of Mizuno and Bernard, LIMK1 has emerged as a key effector in signal transduction pathways downstream of the Rho family of small GTPases and is now recognized for its importance in multiple physiological and pathological contexts.

Molecular Structure and Gene Information

The LIMK family consists of two highly homologous members: LIMK1 and LIMK2. These kinases share 50% amino acid sequence identity overall and 70% within the kinase domain. LIMK1 is encoded by a gene located on chromosome 7q11.23 and can be alternatively spliced into two transcript variants. Its protein structure comprises two LIM domains, a PDZ domain, a serine/proline-rich region, and a kinase domain. The LIM domains, each containing two zinc fingers, mediate protein–protein interactions, while the PDZ domain facilitates subcellular localization and nuclear-cytoplasmic shuttling. The kinase domain features an atypical motif (DLNSHN), enabling LIMK1 to phosphorylate not only serine/threonine residues but also tyrosine residues.

Expression Profile and Cellular Localization

LIMK1 exhibits tissue-specific expression, with particularly high levels in the brain, heart, skeletal muscle, kidney, and lung. This distribution suggests its prominent roles in neural development, cardiac function, and organogenesis. At the subcellular level, LIMK1 can shuttle between the nucleus and cytoplasm, although its kinase activity is predominantly associated with the cytoplasm, where it influences actin cytoskeleton remodeling.

Activation and Downstream Signaling

LIMK1 is a downstream target of Rho GTPases such as Rho, Rac, and Cdc42. These GTPases modulate LIMK1 activity through effectors like ROCK (Rho-associated coiled-coil kinase), PAKs (p21-activated kinases), and MRCKs (myotonic dystrophy kinase-related Cdc42-binding kinases). Phosphorylation at Thr508 is a critical activation step that enhances LIMK1's kinase function. Upon activation, LIMK1 phosphorylates cofilin family proteins at Ser3, including cofilin1, cofilin2, and ADF (actin depolymerizing factor). Phosphorylation inactivates cofilin, stabilizes filamentous actin (F-actin), and promotes stress fiber formation, thereby reshaping cytoskeletal architecture and altering cell morphology and motility.

Figure 1. Cofilin regulation by LIM kinases. (Villalonga E, et al., 2023)

Role in Cytoskeletal Remodeling

LIMK1 is primarily known for regulating actin dynamics, but recent studies suggest it may also influence microtubule stability and turnover, although the precise molecular mechanisms remain under investigation. By orchestrating the balance between globular (G) and filamentous (F) actin, LIMK1 indirectly affects various cellular processes such as cell migration, polarity, adhesion, and mitosis.

Pathological Implications and Therapeutic Relevance

Dysregulation of LIMK1 is implicated in several human diseases, especially those involving cytoskeletal dysfunction, such as neurological disorders (e.g., Fragile X Syndrome), cancer, and glaucoma. Overexpression of LIMK1 leads to abnormal accumulation of F-actin and disrupted cell architecture. In neurons, altered LIMK1 activity affects synaptic stability and plasticity, which are critical in cognitive function. In oncology, LIMK1 is involved in cancer cell invasion and metastasis due to its role in enhancing cell motility.

Given these roles, LIMK1 represents a promising therapeutic target. Inhibitors of LIMK1 have demonstrated potential in preclinical models of cancer, CNS diseases, and fibrotic disorders. However, early inhibitors often suffered from poor specificity and pharmacokinetics. Recent drug discovery efforts have yielded more selective LIMK1 inhibitors, some of which have been profiled using biochemical assays (e.g., RapidFire mass spectrometry for cofilin phosphorylation) and cellular assays (e.g., NanoBRET and AlphaLISA). These studies have helped identify lead compounds with favorable in vitro and in vivo profiles, accelerating the path toward clinical application.

Future Perspectives

The dual substrate specificity and unique domain structure of LIMK1 make it a particularly interesting kinase for drug development. Besides directly targeting the kinase domain, emerging strategies also aim to disrupt its interactions with upstream regulators or downstream substrates, offering broader avenues for therapeutic intervention. Moreover, structure-based drug design, aided by recent insights into LIMK1's conformational dynamics, may yield allosteric inhibitors with higher specificity and better safety profiles.

In conclusion, LIMK1 functions at the intersection of cytoskeletal dynamics and signal transduction, influencing a range of cellular behaviors that are central to development and disease. Continued elucidation of its molecular mechanisms and the development of potent, selective inhibitors are likely to open new doors for the treatment of complex diseases associated with cytoskeletal dysregulation.

References

Villalonga E, Mosrin C, Normand T, et al. LIM Kinases, LIMK1 and LIMK2, Are Crucial Node Actors of the Cell Fate: Molecular to Pathological Features. Cells. 2023 Mar 4;12(5):805.
Chatterjee D, Preuss F, Dederer V, et al. Structural Aspects of LIMK Regulation and Pharmacology. Cells. 2022 Jan 2;11(1):142.

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