LIMK1 (LIM domain kinase 1)

2009-08-01   Ratna Chakrabarti 

Department of Molecular biology, Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, USA

Identity

HGNC
LOCATION
7q11.23
IMAGE
Atlas Image
LEGEND
LIMK1 gene is located at chromosome 7 on the long arm (q11.23).
LOCUSID
ALIAS
LIMK,LIMK-1
FUSION GENES

DNA/RNA

Atlas Image
A) LIMK1 gene consists of 16 exons. Exons 2-4 encode two LIM domains in tandem. Exons 4-6 encode a PDZ domain and exons 8-16 encode a serine/threonine kinase domain. B) A splice variant of LIMK1 (dLIMK1), which lacks the kinase domain. In this variant, intron 7 was extended to 61 additional bases at the 5 end of exon 8, which caused a frameshift in the LIMK1 ORF and resulted in premature termination after 12 missense mutations in dLIMK1.

Description

The gene starts at 73136092 bp from pter and ends at 73174790 bp from pter. Its size is 38699 bases and its orientation lie in the plus strand. The 5 promoter region (1.5 kb) contains putative sites for transcriptional regulation including Sp1, MZF1, AP1 and NF-E2. No consensus TATA box is evident.

Transcription

The transcript contains 16 exons spanning a length of 3.332 kb. The mRNA contains a short 5UTR but a long 3 end UTR. Two LIM domains, LIM1 and LIM2 are encoded by the exons 2-4. A single PDZ domain is encoded by the exons 2-6. A C-terminal domain is encoded by exons 8-16.

Pseudogene

None identified.

Proteins

Atlas Image
LIMK1 consists of specific domains, nuclear localisation signal (NLS) and nuclear exit signals (NES).

Description

The LIMK1 protein is composed of 647 amino acids. It belongs to a unique family of LIM domain containing dual specificity (serine threonine and tyrosine) protein kinase. LIMK1 also has a PDZ domain in the middle of the gene and a kinase domain at the C-terminal end. A stretch of basic amino acids resembling nuclear localisation signal is present in the kinase domain and two nuclear export signal sequences containing hydrophobic residues are present in the PDZ domain.

Expression

LIMK1 exhibits tissue specific expression. It is predominantly expressed in brain but to a moderate extent in the heart and skeletal muscle. The least amount of LIMK1 expression was noted in the liver. LIMK1 is also expressed in lesser amounts in various human epithelial cell lines and haematopoetic cell lines.

Localisation

LIMK1 is primarily localized in the cytoplasm but also transported to the nucleus. In the cytoplasm, LIMK1 is colocalized with microtubules, and actin at the focal adhesion, stress fiber and at the lamellipodia. In the mitotic cells, LIMK1 is localized to the centrosomes until early telophase and to the cleavage furrow during late telophase.

Function

LIMK1 regulates organization of actin cytoskeleton through inactivating phosphorylation of the actin depolymerizing family (ADF) protein cofilin. LIMK1 phosphorylates cofilin at Serine, which inhibits actin depolymerization and results in accumulation of F actin. LIMK1 also regulates microtubule stability and assembly through phosphorylation of p25/TPPP (tubulin polymerization protein), which destabilizes microtubules. Activated LIMK1 associates with gamma-tubulin at the centrosome during mitotic phases. LIMK1 is a multifunctional protein and is involved in regulation of cell motility, cell cycle, cytokinesis and cellular morphology. LIMK1 also regulates neurite growth, synaptic stability, growth cone motility, axon formation through modulation of Golgi dynamics and neuronal differentiation.

Homology

LIMK1 has 50% identity overall and 70% identity in the kinase domain with another family member LIMK2. Although both proteins phosphorylate cofilin and regulate actin cytosketon reorganization current studies showed that LIMK2 has also different cellular function.

Mutations

Germinal

Hemizygous deletion of LIMK1 along with Elastin gene in a 1.5 MB deletion has been noted in patients with Williams-Beuren syndrome. Patients with Williams Syndrome exhibit impaired visuospatial constructive cognition possibly because of loss of LIMK1 gene.
SNP: A single nucleotide polymorphism of LIMK1 in a haplotype spanning Elastin gene has been linked to susceptibility of intracranial aneurysm (IA).

Implicated in

Entity name
Prostate cancer
Disease
Prostate cancer is the most prevalent malignancy second to lung cancer in men in the western world. Although slow growing, a subpopulation of prostate cancer patients develops highly invasive metastatic disease that is nonresponsive to anti-androgen therapy and is usually fatal.
Prognosis
The gold standard for diagnosis of prostate cancer are the Gleason scores and the serum PSA level. PSA level is also used for prognostic purposes. LIMK1 expression may have prognostic value for identification of metastatic progression as overexpression of LIMK1 has been noted in metastatic prostate cancer cells.
Cytogenetics
Through cytogenetics method such as CGH and FISH analysis chromosomal gain in 7q11.2 region or entire chromosome 7 including 7q11.23 locus has been reported in some prostate cancer cases.
Oncogenesis
LIMK1 is overexpressed in prostate cancer cells and tissues compared to benign prostatic hyperplasia. Because LIMK1 plays an important role in mitosis, microtubule dynamics and cytokinesis altered expession of LIMK1 may cause mitotic defects. Aberrant expression of LIMK1 is also involved in induction of invasion in prostate cancer cells.
Entity name
Breast cancer
Disease
Breast cancer is one of the major cancers affecting women in the western world after skin cancer and second leading cause of cancer death in women. About 20% of breast cancers are familial and about 10% of breast cancer is because of inheritence of a mutated gene. Although the cure rate has been increased because of the improved diagnostic approaches and early detection, the metastatic disease actually has been increased since 1990.
Prognosis
Overexpression of Her2/neu oncogene product is considered to be associated with worse prognosis. LIMK1 expression may have a prognostic value for metastatic breast cancer as overexpression of LIMK1 has been noted in metastatic breast cancer cells.
Cytogenetics
CGH analysis indicated a gain in chromosome 7 in majority of the infiltrating ductal carcinoma cases. Some of the chromosomal gains include the region encompassing Elastin and LIMK1 loci.
Oncogenesis
Overexpression of LIMK1 has been shown to increase invasion and metastasis in animals. LIMK1 also involved in regulation of EGFR turnover through endocytic pathway in invasive breast cancer cells, which may have implication in development of an agressive disease.
Entity name
Melanoma
Disease
Malignant melanoma is an agressive type of skin cancer, which often metastasize leading to death. The progression of melanoma is unpredictable and sometimes show refractoriness to available chemotherapy.
Cytogenetics
Chromosomal analysis using tiling array and CGH showed a gain in chromosome 7 in melanoma cells. Increased expression of LIMK1 in melanoma cells (Skmel 28) harboring a break at 7q11.2 has also been reported.
Entity name
Williams-Beuren Syndrome (WBS)
Disease
WBS is a genetic disorder with autosomal dominant inheritence. WBS is caused by microdeletion at 7q11.23 region with a phenotype of connective tissue abnormalities, growth and psychomotor retardation, muscular hypotonia, loss of visuospatial cognition and behavioural abnormalities.
Prognosis
The presence of supravalvular aortic stenosis, pulmonary stenosis, developmental retardation and characteristic facial features in children between 18 to 30 months.
Cytogenetics
Chromosome analyses showed a deletion at the LIMK1 locus at 7q11.23 caused by a distal recombination event at the common telomeric breakpoint.
Entity name
Alzheimer Disease (AD)
Disease
Dystrophic neurites are found to be associated with Alzheimers pathology. Altered structures of axons and dendrites, deposition of amyloid plaques leading to neurofibrillary tangle formation in AD pathology are responsible for dementia and cognitive disorder in Alzheimers patients.
Prognosis
Deposition of fibrillar amyloid beta in the brain is one of the events towards developing Alzheimer Disease. LIMK1 has been shown to be involved in amyloid beta-induced neuronal degeneration. Immunofluorescence analysis showed an increased number of phosphorylated LIMK1 positive neurons in the areas of brain with AD pathology. Inhibition of cofilin phosphorylation prevented neuronal degeneration, which supports the involvement of LIMK1 in AD.
Entity name
Intracranial Aneurysm
Disease
Intracranial aneurysm is the localized dilation of the blood vessel which could be fatal upon rupture causing hemorrhage in the subarachnoid space. It occurs more frequently in adults than children and in women than men. Risk factors include family history of aneurysm and inherited disorders including polycystic kidney disease.
Cytogenetics
Genome wide linkage studies indicated a significant association between SNP in LIMK1 promoter sequence at 7q11.2 locus and incidence of IA in Japanese and Korean patients. The SNP in the promoter sequence of LIMK1 [C(-187)T] introduced an additional transcription factor (AP2) binding site, which leads to a reduced transcription of LIMK1 mRNA.

Bibliography

Pubmed IDLast YearTitleAuthors
166116742006A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms.Akagawa H et al
108797432000Identification of genetic markers for prostatic cancer progression.Alers JC et al
163810002006LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase-type plasminogen activator system.Bagheri-Yarmand R et al
180003992007Phosphorylated LIM kinases colocalize with gamma-tubulin in centrosomes during early stages of mitosis.Chakrabarti R et al
128216642003LIM kinase 1 is essential for the invasive growth of prostate epithelial cells: implications in prostate cancer.Davila M et al
161293992005LIM Kinase1 controls synaptic stability downstream of the type II BMP receptor.Eaton BA et al
101962271999Structural features of LIM kinase that control effects on the actin cytoskeleton.Edwards DC et al
126844372003Control of growth cone motility and morphology by LIM kinase and Slingshot via phosphorylation and dephosphorylation of cofilin.Endo M et al
158971902005LIM kinase 1 coordinates microtubule stability and actin polymerization in human endothelial cells.Gorovoy M et al
167751412006Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid beta-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer's disease.Heredia L et al
91503881997Inhibition of activated Ras-induced neuronal differentiation of PC12 cells by the LIM domain of LIM-kinase 1.Higuchi O et al
94850321998A molecular cytogenetic analysis of 7q31 in prostate cancer.Jenkins RB et al
172600122007Genomic profiling of malignant melanoma using tiling-resolution arrayCGH.Jönsson G et al
81835541994Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif.Mizuno K et al
167638282006A role of LIM kinase 1/cofilin pathway in regulating endocytic trafficking of EGF receptor in human breast cancer cells.Nishimura Y et al
159671072005Seven novel and stable translocations associated with oncogenic gene expression in malignant melanoma.Okamoto I et al
150906202004LIMK1 regulates Golgi dynamics, traffic of Golgi-derived vesicles, and process extension in primary cultured neurons.Rosso S et al
86731241996LIM-kinase deleted in Williams syndrome.Tassabehji M et al
127776192003A role for LIM kinase in cancer invasion.Yoshioka K et al

Other Information

Locus ID:

NCBI: 3984
MIM: 601329
HGNC: 6613
Ensembl: ENSG00000106683

Variants:

dbSNP: 3984
ClinVar: 3984
TCGA: ENSG00000106683
COSMIC: LIMK1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000106683ENST00000336180P53667
ENSG00000106683ENST00000418310E9PC47
ENSG00000106683ENST00000435201P53667
ENSG00000106683ENST00000538333P53667

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Axon guidanceKEGGko04360
Regulation of actin cytoskeletonKEGGko04810
Axon guidanceKEGGhsa04360
Regulation of actin cytoskeletonKEGGhsa04810
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Fcgamma receptor (FCGR) dependent phagocytosisREACTOMER-HSA-2029480
Regulation of actin dynamics for phagocytic cup formationREACTOMER-HSA-2029482
Signal TransductionREACTOMER-HSA-162582
Signaling by Rho GTPasesREACTOMER-HSA-194315
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases Activate ROCKsREACTOMER-HSA-5627117
RHO GTPases activate PAKsREACTOMER-HSA-5627123
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Semaphorin interactionsREACTOMER-HSA-373755
Sema4D in semaphorin signalingREACTOMER-HSA-400685
Sema4D induced cell migration and growth-cone collapseREACTOMER-HSA-416572
Sema3A PAK dependent Axon repulsionREACTOMER-HSA-399954
EPH-Ephrin signalingREACTOMER-HSA-2682334
EPHB-mediated forward signalingREACTOMER-HSA-3928662

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
172942302007LIM kinases: function, regulation and association with human disease.102
156601332005Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin.94
127776192003A role for LIM kinase in cancer invasion.68
152209302004LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1.67
128216642003LIM kinase 1 is essential for the invasive growth of prostate epithelial cells: implications in prostate cancer.54
184240722008A PAK4-LIMK1 pathway drives prostate cancer cell migration downstream of HGF.54
213211232011LIM kinase 1 modulates cortical actin and CXCR4 cycling and is activated by HIV-1 to initiate viral infection.45
163810002006LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase-type plasminogen activator system.41
158971902005LIM kinase 1 coordinates microtubule stability and actin polymerization in human endothelial cells.40
162041832005The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones.40

Citation

Ratna Chakrabarti

LIMK1 (LIM domain kinase 1)

Atlas Genet Cytogenet Oncol Haematol. 2009-08-01

Online version: http://atlasgeneticsoncology.org/gene/41159/limk1