Disease relevance of Limk1

• In addition, abnormal expression of LIMK-1 is associated with Williams syndrome, a mental disorder with profound deficits in visuospatial cognition [1].
• LIM kinase 1 (LIMK1) controls important cellular functions such as morphogenesis, cell motility, tumor cell metastasis, development of neuronal projections, and growth cone actin dynamics [2].
• We found that the level and activity of endogenous LIMK1 is increased in invasive breast and prostate cancer cell lines in comparison with less invasive cells [3].
• Overexpression of LIMK1 in MCF-7 and in MDA-MB-231 human breast cancer cell lines increased their motility, whereas the specific ROCK and Rho inhibitors Y-27632 and C3, respectively, attenuated this effect [3].

High impact information on Limk1

• Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons [2].
• Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (HF) [4].
• LIM kinase 1 regulates actin filament dynamics through inhibition of ADF/cofilins [5].
• Using LIMK-1 knockout mice, we demonstrate a significant role for LIMK-1 in vivo in regulating cofilin and the actin cytoskeleton [1].
• In vitro studies indicate a role for the LIM kinase family in the regulation of cofilin phosphorylation and actin dynamics [1].

Biological context of Limk1

• Exon/intron boundaries of the mouse Limk2a gene are exactly conserved with those of the mouse Limk1 gene [6].
• Regulation of ADF/cofilin phosphorylation and synaptic function by LIM-kinase [7].
• We have isolated the murine Limk1 gene, which is a single copy gene located at the distal end of mouse chromosome 5 [8].
• We have cloned and characterized the mouse gene encoding Kiz1/Limk1, a new member of the zinc-finger LIM family that also has a kinase domain [9].
• LIM-kinase as a regulator of actin dynamics in spermatogenesis [10].

Anatomical context of Limk1

• Head, neck, and spines: a role for LIMK-1 in the hippocampus [5].
• These results indicate that LIMK-1 plays a critical role in dendritic spine morphogenesis and brain function [1].
• Moreover, high levels of limk expression is associated with the overt formation of giant cells from diploid progenitors, suggesting an involvement for limk in the differentiation of this highly specialized extra-embryonic cell type [11].
• Additionally we have shown that limk is most abundantly expressed in the trophoblast giant cells, from 4.5 d.p.c. onwards [11].
• By 10.0 d.p.c. limk remains prominently expressed in the ventromedial regions of the developing forebrain and midbrain, with continued expression in the hindgut [11].

Associations of Limk1 with chemical compounds

• Limk1 is predominantly expressed in neural tissues and phosphorylates serine, threonine and tyrosine residues in vitro [8].
• Although Limk1 and LIMK contain all motifs found in catalytic kinase domains, amino acids previously described to be diagnostic of either serine/threonine- or tyrosine-kinases are not present [8].
• LIM-kinase 1 (LIMK1) is a serine/threonine kinase containing two LIM motifs at the N-terminus [12].

Other interactions of Limk1

• The murine LIM-kinase gene (limk) encodes a novel serine threonine kinase expressed predominantly in trophoblast giant cells and the developing nervous system [11].
• Rac1-induced caspase-1 activation was mediated by its effect on LIM kinase-1, which is targeting the actin cytoskeleton [13].
• The recent findings that knockout mice lacking LIMK1 or CLIP-115 have distinct neurological and behavioural phenotypes, indicates that cytoskeletal defects might play a role in the development of neurological symptoms in Williams Syndrome patients [14].
• Transfection of LIMK1 sense cDNA into NIH3T3 and H-ras-transformed FYJ10 fibroblasts significantly suppressed colony formation of these cells [12].

Analytical, diagnostic and therapeutic context of Limk1

• Assignment of the human and mouse LIM-kinase genes (LIMK1; Limk1) to chromosome bands 7q11.23 and 5G1, respectively, by in situ hybridization [15].
• Immunofluorescence analysis demonstrated LIMK1 subcellular localization at focal adhesions in fibroblasts as revealed by co-staining with actin, paxillin and vinculin in addition to perinuclear (Golgi) and occasional nuclear localization [16].
• Immunoblotting analysis revealed widespread expression of LIMK1 existing as a 70-kDa protein in tissues and in cell lines, with a higher mass form (approximately 75 kDa) present in some tissues and cell lines [16].
• Furthermore, an association between LIMK1 and paxillin but not vinculin was identified by co-immunoprecipitation analysis [16].
• In addition, inhibition of LIMK1 activity in the MDA-MB-231 cells by expression of dominant-negative LIMK1 resulted in decreased motility and formation of osteolytic bone lesions in an animal model of tumor invasion [3].

References