Download Gene Section LIMK1 (LIM domain kinase 1) Atlas of Genetics and Cytogenetics

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Gene Section
Review
LIMK1 (LIM domain kinase 1)
Ratna Chakrabarti
Department of Molecular biology and Microbiology, Burnett School of Biomedical Sciences, University of
Central Florida, 12722 Research Parkway, Orlando, Florida 32826, USA (RC)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/LIMK1ID41159ch7q11.html
DOI: 10.4267/2042/44796
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Transcription
Other names: EC 2.7.11.1; LIMK; LIMK-1
HGNC (Hugo): LIMK1
Location: 7q11.23
Local order: ELN, LIMK1, EIF4H, LAT2.
The transcript contains 16 exons spanning a length of
3.332 kb. The mRNA contains a short 5'UTR 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.
Protein
Description
LIMK1 gene is located at chromosome 7 on the long arm
(q11.23).
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.
DNA/RNA
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.
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.
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LIMK1 (LIM domain kinase 1)
Chakrabarti R
LIMK1 consists of specific domains, nuclear localisation signal (NLS) and nuclear exit signals (NES).
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).
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.
Implicated in
Localisation
Prostate cancer
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.
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.
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.
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
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
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LIMK1 (LIM domain kinase 1)
Chakrabarti R
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.
Alzheimer's 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
Alzheimer's 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.
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.
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.
Williams-beuren syndrome (WBS)
References
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.
Mizuno K, Okano I, Ohashi K, Nunoue K, Kuma K, Miyata T,
Nakamura T. Identification of a human cDNA encoding a novel
protein kinase with two repeats of the LIM/double zinc finger
motif. Oncogene. 1994 Jun;9(6):1605-12
Tassabehji M, Metcalfe K, Fergusson WD, Carette MJ, Dore
JK, Donnai D, Read AP, Pröschel C, Gutowski NJ, Mao X,
Sheer D. LIM-kinase deleted in Williams syndrome. Nat Genet.
1996 Jul;13(3):272-3
Higuchi O, Amano T, Yang N, Mizuno K. Inhibition of activated
Ras-induced neuronal differentiation of PC12 cells by the LIM
domain of LIM-kinase 1. Oncogene. 1997 Apr 17;14(15):181925
Jenkins RB, Qian J, Lee HK, Huang H, Hirasawa K, Bostwick
DG, Proffitt J, Wilber K, Lieber MM, Liu W, Smith DI. A
molecular cytogenetic analysis of 7q31 in prostate cancer.
Cancer Res. 1998 Feb 15;58(4):759-66
Edwards DC, Gill GN. Structural features of LIM kinase that
control effects on the actin cytoskeleton. J Biol Chem. 1999
Apr 16;274(16):11352-61
Alzheimer disease (AD)
Alers JC, Rochat J, Krijtenburg PJ, Hop WC, Kranse R,
Rosenberg C, Tanke HJ, Schröder FH, van Dekken H.
Identification of genetic markers for prostatic cancer
progression. Lab Invest. 2000 Jun;80(6):931-42
Disease
Dystrophic neurites are found to be associated with
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7)
643
LIMK1 (LIM domain kinase 1)
Chakrabarti R
Davila M, Frost AR, Grizzle WE, Chakrabarti R. LIM kinase 1 is
essential for the invasive growth of prostate epithelial cells:
implications in prostate cancer. J Biol Chem. 2003 Sep
19;278(38):36868-75
Kimm K, Inoue I. A haplotype spanning two genes, ELN and
LIMK1, decreases their transcripts and confers susceptibility to
intracranial aneurysms. Hum Mol Genet. 2006 May
15;15(10):1722-34
Endo M, Ohashi K, Sasaki Y, Goshima Y, Niwa R, Uemura T,
Mizuno K. Control of growth cone motility and morphology by
LIM kinase and Slingshot via phosphorylation and
dephosphorylation of cofilin. J Neurosci. 2003 Apr
1;23(7):2527-37
Bagheri-Yarmand R, Mazumdar A, Sahin AA, Kumar R. LIM
kinase 1 increases tumor metastasis of human breast cancer
cells via regulation of the urokinase-type plasminogen activator
system. Int J Cancer. 2006 Jun 1;118(11):2703-10
Heredia L, Helguera P, de Olmos S, Kedikian G, Solá Vigo F,
LaFerla F, Staufenbiel M, de Olmos J, Busciglio J, Cáceres A,
Lorenzo
A.
Phosphorylation
of
actin-depolymerizing
factor/cofilin by LIM-kinase mediates amyloid beta-induced
degeneration: a potential mechanism of neuronal dystrophy in
Alzheimer's disease. J Neurosci. 2006 Jun 14;26(24):6533-42
Yoshioka K, Foletta V, Bernard O, Itoh K. A role for LIM kinase
in cancer invasion. Proc Natl Acad Sci U S A. 2003 Jun
10;100(12):7247-52
Rosso S, Bollati F, Bisbal M, Peretti D, Sumi T, Nakamura T,
Quiroga S, Ferreira A, Cáceres A. LIMK1 regulates Golgi
dynamics, traffic of Golgi-derived vesicles, and process
extension in primary cultured neurons. Mol Biol Cell. 2004
Jul;15(7):3433-49
Nishimura Y, Yoshioka K, Bernard O, Bereczky B, Itoh K. A
role of LIM kinase 1/cofilin pathway in regulating endocytic
trafficking of EGF receptor in human breast cancer cells.
Histochem Cell Biol. 2006 Nov;126(5):627-38
Eaton BA, Davis GW. LIM Kinase1 controls synaptic stability
downstream of the type II BMP receptor. Neuron. 2005 Sep
1;47(5):695-708
Chakrabarti R, Jones JL, Oelschlager DK, Tapia T, Tousson A,
Grizzle WE. Phosphorylated LIM kinases colocalize with
gamma-tubulin in centrosomes during early stages of mitosis.
Cell Cycle. 2007 Dec 1;6(23):2944-52
Gorovoy M, Niu J, Bernard O, Profirovic J, Minshall R, Neamu
R, Voyno-Yasenetskaya T. LIM kinase 1 coordinates
microtubule stability and actin polymerization in human
endothelial cells. J Biol Chem. 2005 Jul 15;280(28):26533-42
Jönsson G, Dahl C, Staaf J, Sandberg T, Bendahl PO, Ringnér
M, Guldberg P, Borg A. Genomic profiling of malignant
melanoma using tiling-resolution arrayCGH. Oncogene. 2007
Jul 12;26(32):4738-48
Okamoto I, Pirker C, Bilban M, Berger W, Losert D, Marosi C,
Haas OA, Wolff K, Pehamberger H. Seven novel and stable
translocations associated with oncogenic gene expression in
malignant melanoma. Neoplasia. 2005 Apr;7(4):303-11
This article should be referenced as such:
Chakrabarti R. LIMK1 (LIM domain kinase 1). Atlas Genet
Cytogenet Oncol Haematol. 2010; 14(7):641-644.
Akagawa H, Tajima A, Sakamoto Y, Krischek B, Yoneyama T,
Kasuya H, Onda H, Hori T, Kubota M, Machida T, Saeki N,
Hata A, Hashiguchi K, Kimura E, Kim CJ, Yang TK, Lee JY,
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7)
644