ILK (integrin-linked kinase)

2014-08-01   Isabel Serrano  , Paul McDonald  , Shoukat Dedhar  

Department of Integrative Oncology, British Columbia Cancer Research Centre of the BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC, Canada, V5Z1L3

Identity

HGNC
LOCATION
11p15.4
LOCUSID
ALIAS
HEL-S-28,ILK-1,ILK-2,P59,p59ILK
FUSION GENES

Abstract

Review on ILK (integrin-linked kinase), with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Atlas Image
Chromosome 11, genomic organization of human ILK. The ILK gene is located on chromosome 11 at position 15. Exactly from 6624961 bp to 6632102 bp (7142 bases) (Diagram author: Elena Serrano).

Description

According to Entrez-Gene, human ILK maps to locus NC_000011.9. ILK gene contains 13 exons and spans 9.0 kb.

Transcription

ILK encodes a predicted 451-amino acid protein with an apparent molecular mass of 59 kD based on SDS-PAGE. Northern blot analysis showed that the 1.8-kb ILK mRNA is widely expressed.

Pseudogene

An ILK pseudogene has been found in mice, predicted gene 6263 (Gm6263).

Proteins

Atlas Image
Functional domains of integrin-linked kinase (ILK). ILK is an intracellular serine/threonine protein kinase with a C-terminal kinase catalytic domain. ILK structure consists in four ankyrin repeats at the N-terminus (residues 33-164), a phosphoinositide-binding motif and a catalytic domain (residues 180-212). The integrin-binding site is in the extreme C-terminus of the kinase domain (residues 293-451) (Diagram author: Elena Serrano).

Description

ILK is a widely expressed modular protein composed of three major domains: an N-terminal domain that contains four ankyrin repeats, a central pleckstrin homology (PH)-like domain and a C-terminal kinase domain. The N-terminal ankyrin domain binds to PINCH (particularly interesting new cysteinehistidine protein) - an adaptor protein that complexes with ILK in the cytoplasm prior to active recruitment of ILK to focal adhesion sites - and to ILK-associated protein (ILKAP) - a protein phosphatase 2C (PP2C)-family protein phosphatase that negatively regulates ILK signaling (McDonald et al., 2008a). Adjacent to the ankyrin repeats, a sequence motif present in PH domains binds to the second messenger PI(3,4,5)P3 and a PI3-kinase-dependent kinase activation has been reported (Delcommenne et al., 1998; Boulter and Van Obberghen-Schilling, 2006). The C-terminus kinase domain also interacts with integrins, as well as with the focal adhesion proteins paxillin (Nikolopoulos and Turner, 2001; Nikolopoulos and Turner, 2002) and parvins (Hannigan et al., 2005; Legate et al., 2006), which link ILK, and therefore integrins, to the actin cytoskeleton.

Expression

ILK is ubiquitously expressed in most tissues, with predominance at skeletal muscle, heart, kidney and pancreas. Increased expression of ILK is correlated with progression of several tumor types, constituting an attractive therapeutic target in human cancer.

Localisation

ILK is generally considered a cytosolic protein localized at focal adhesions, however ILK co-localizes with tubulins and many centrosomal and mitotic spindle associated proteins at centrosomes.

Function

Integrin-linked kinase (ILK) (Hannigan et al., 1996) is a multifunctional protein kinase which is implicated in a large number of cellular processes and diseases, participating in signal transduction pathways that control cell survival, differentiation, proliferation and gene expression in mammalian cells (Wu, 2001). ILK, PINCH1 and α-parvin form a ternary complex termed IPP (ILK-PINCH-parvin) that localizes to both focal adhesions (FAs) and fibrillar adhesions (FBs) and is essential for several integrin-dependent functions. The IPP complex, interacts with the cytoplasmic tail of β integrins, resulting in the engagement and organization of the cytoskeleton as well as activation of signalling pathways. Deletion of the genes encoding ILK or PINCH1 similarly blocks maturation of FAs and FBs by downregulating expression or recruitment of tensin and destabilizing α5β1-integrin-cytoskeleton linkages (Legate et al., 2006; Stanchi et al., 2009; Elad et al., 2013). The kinase activity of ILK is stimulated by integrins and soluble mediators, including growth factors and chemokines, and is regulated in a phosphoinositide 3-kinase (PI3K)-dependent manner. The activity of ILK is antagonized by phosphatases such as ILKAP and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (McDonald et al., 2008a). Important downstream targets of ILK signaling include PKB/Akt, GSK-3, β-catenin, p44/p42 MAP kinases, the myosin light chain (MLC) (Hannigan et al., 2011) and the Hippo pathway through Merlins phosphatase MYPT1 (Serrano et al., 2013c). AKT is a regulator of cell survival and apoptosis. To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473. Phosphorylation at serine 473 depends on PI3K activity (Persad et al., 2001), the rictor-mTOR complex (Sarbassov et al., 2005) and the ILK-Rictor complex (McDonald et al., 2008b). GSK-3 is phosphorylated and inactivated at serine 9 by ILK, regulating the cell cycle through proteolysis of cyclin D1 and activation of the transcription factor AP1 (Troussard et al., 1999). Inactivation of GSK-3 stabilizes β-catenin, whose accumulation is related to deregulation of proliferation, migration and differentiation (Oloumi et al., 2004). ILK can directly phosphorylate MLC on Ser18/thr19 influencing in cell contraction, motility and migration (Deng et al., 2001). ILK function is required in TGFβ-1-induced EMT in mammary epithelial cells, and the ILK/Rictor complex has been identified as a potential molecular target for preventing/reversing EMT (Serrano et al., 2013b). But ILK can also directly regulate EMT by promoting the expression of Snail transcriptionally (McPhee et al., 2008) and via posttranslational modification through GSK-3b.
ILK also localize to centrosomes, where it is recruited by RUVBI1/2, and it regulates mitotic spindle assembly by promoting Aurora A kinase/TACC3/ch-TOG interactions (Fielding et al., 2008) as well as centrosome clustering through the microtubule regulating proteins TACC3 and ch-TOG (Fielding et al., 2011). In addition, ILK regulates microtubule dynamics since overexpression of ILK in HeLa cells is associated with a shorter duration of mitosis and decreased sensitivity to paclitaxel, a chemotherapeutic agent that suppresses microtubule dynamics and conversely, the use of a small molecule inhibitor selective against ILK, QLT-0267, results in suppressed microtubule dynamics (Lim et al., 2013). ILK regulation of microtubules is critical for proper trafficking of caveolin-1-containing vesicles. ILK controls this process by regulating microtubule stability through the recruitment of the scaffold protein IQGAP1 and its downstream effector mDia1 to nascent, cortical adhesion sites. In the absence of ILK, caveolae remain associated with dynamic microtubules, fail to stably fuse with the plasma membrane, and subsequently accumulate in intracellular structures (Wickström et al., 2010).
Atlas Image
ILK interaction partners. Schematic representation of the signal transduction pathways where ILK is implicated. Dark green represents direct interaction, red represents indirect interaction and light brown represents not analysed. Adapted from Widmaier et al., 2012 by Elena Serrano.

Homology

The ILK gene is highly conserved in a total of 24 species. The most representatives are human, mouse, chicken, lizard, African clawed frog, zebrafish, fruit fly, worm.

Mutations

Note

1. ILK mutation causes human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells (Knoll et al., 2007).
2. Embryonic lethality was observed in Xenopus laevis (Yasunaga et al., 2005) and mouse (Sakai et al., 2003) models of ILK ablation, and this was attributed to defects in adhesive and migratory mechanics.

Implicated in

Entity name
Melanoma
Note
Increased expression of integrin-linked kinase is correlated with melanoma progression and poor patient survival (Dai et al., 2003; Wong et al., 2007). ILK regulates melanoma angiogenesis by activating NF-kB/interleukin-6 signaling pathway (Wani et al., 2011).
Entity name
Colon cancer
Note
ILK is hyperexpressed in malignant crypts from both the primary and metastatic lesions. Changes in ILK activity coincide with changes on downstream targets, primarily GSK3β. Dysregulation of the ILK-signaling nexus is an important early event in the genesis of human colon cancer (Marotta et al., 2003). ILK expression levels correlated with tumor invasion, grade and stage; higher levels in metastatic tumors (Bravou et al., 2003). Thymosin beta 4 induces colon cancer cell migration and clinical metastasis via enhancing ILK/IQGAP1/Rac1 signal transduction pathway (Tang et al., 2011).
Entity name
Gastric cancer
Note
ILK might be a novel molecular marker for aggressive gastric cancer. Strong expression of ILK is observed in the majority of primary tumors that were associated with tumor cell invasion and nodal metastasis; no expression in non-neoplastic gastric epithelia (Ito et al., 2003). ILK might be used as a potential therapeutic strategy to combat multi-drug resistance through blocking PI3K-Akt and MAPK-ERK pathways in human gastric carcinoma (Song et al., 2012).
Entity name
Lung cancer
Note
ILK expression is significantly associated with tumor grade and stage, and lower than 5-year survival. Increased expression of ILK is a poor prognostic factor in patients with non-small cell lung cancer (Takanami 2005; Okamura et al., 2007).
Entity name
Anaplastic thyroid cancer
Note
ILK is a potential therapeutic target for treating anaplastic thyroid cancer. ILK expression and activity are elevated in human anaplastic thyroid cancer and ILK inhibition leads to growth arrest and apoptosis in vitro and in vivo (Younes et al., 2005).
Entity name
Squamous cell carcinoma of head and neck
Note
ILK is overexpressed in SCCHN tumor specimens. Targeting ILK with the small-molecule ILK inhibitor QLT0267 inhibits cell growth and induces apoptosis in SCCHN cell lines by reducing ILK activity and Akt phosphorylation (Younes et al., 2007).
Entity name
Pancreatic cancer
Note
ILK is involved with aggressive capability in pancreatic cancer. Significant association between strong expression of ILK and poor prognosis of pancreatic cancer patients has been observed (Sawai et al., 2006). Silencing ILK could be a potentially useful therapeutic approach for treating pancreatic cancer (Schaeffer et al., 2010; Zhu et al., 2012).
Entity name
Ovarian cancer
Note
ILK expression is increased with tumor progression; normal epithelium was negative for ILK (Ahmed et al., 2003). ILK gene silencing suppresses tumor growth in human ovarian carcinoma HO-8910 xenografts in mice (Li et al., 2013) and induces apoptosis in ovarian carcinoma SKOV3 cell (Liu et al., 2012).
Entity name
Prostate cancer
Note
ILK expression is increased with tumor progression. Increased expression of the protein has been demonstrated to be inversely related to the 5-year survival rate in prostate cancer (Graff et al., 2001). ILK stimulates the expression of VEGF by stimulating HIF-1alpha protein expression in a PKB/Akt- and mTOR/FRAP-dependent manner and knockdown of ILK expression with siRNA, or inhibition of ILK activity, results in significant inhibition of HIF-1alpha and VEGF expression (Tan el al., 2004). Compound 22, a novel ILK inhibitor, exhibited high in vitro potency against a panel of prostate and breast cancer cell lines and its therapeutic potential has been suggested by its in vivo efficacy as a single oral agent in suppressing PC-3 xenograft tumor growth (Lee et al., 2011).
Entity name
Mesothelioma
Note
ILK is expressed in malignant mesothelioma. Normal mesothelial cells and lung parenchyma are negative (Watzka et al., 2008). Evaluating ILKs potential use as a marker of disease progression in malignant pleural mesothelioma has been suggested (Watzka et al., 2013).
Entity name
Ewings sarcoma and primitive neuroectodermal tumor
Note
Expression is observed (Chung et al., 1998).
Entity name
Glioblastoma
Note
The ILK inhibitor, QLT0267, was able to reduce cellular invasion and angiogenesis of glioma cells. Blocking the ILK/Akt pathway is a potential strategy for molecular targeted therapy for gliomas (Kou et al., 2005; Edwards et al., 2008). Expression of insulin-like growth factor-binding protein 2 (IGFBP2), a glioma oncogene emerging as a target for therapeutic intervention, requires ILK to induce cell motility and activate NF-kB (Holmes et al., 2012).
Entity name
Musculoskeletal sarcoma
Note
Prognostic factor in osteosarcoma and a novel potential therapeutic target for the treatment of osteosarcoma (Rhee et al., 2013).
Entity name
Medulloblastoma
Note
Expression is observed (Chung et al., 1998).
Entity name
Breast cancer, cancer cell growth and metastasis
Note
Epithelial to mesenchymal transition (EMT) causes fibrosis, cancer progression and metastasis. Acquisition of invasive and migratory characteristics in cancer cells results primarily from adopting an EMT phenotype. Overexpression of ILK induces EMT in mammary epithelial cells (Somasiri et al., 2001) and targeting this signaling cascade is an effective strategy for the treatment of fibrotic kidney (Li et al., 2009), lung (Kavvadas et al., 2010) or bladder cancer (Matsui et al., 2011). ILK is a key intracellular mediator of TGFβ-1 induced EMT (Li et al., 2009) through a Snail and Slug mechanism (Serrano et al., 2013b). TGFβ-1 mediated EMT induces an interaction between ILK and Rictor and disruption of this interaction by silencing ILK or using ILK inhibitor molecule, QLT0267, blocks TGFβ-1 induced EMT and partially reverses the mesenchymal phenotype in breast cancer cell lines (Serrano et al., 2013b). ILK promotes lung cancer cell migration and invasion through the induction of EMT process (Chen et al., 2013) and is a therapeutically targetable mediator of ERG-induced EMT and transformation in prostate cancer (Becker-Santos et al., 2012) and in high glucose-induced epithelial-mesenchymal transition of renal tubular cell (Peng et al., 2012). A significant acceleration in mammary tumor incidence and growth was observed in the MMTV-Wnt/ILK mice compared to Wnt alone, showing the cooperation between Wnt1 and ILK transgenes during mammary carcinogenesis (Oloumi et al., 2010). Furthermore, mammary epithelial disruption of ILK in mice results in a profound block in mammary tumor induction (Pontier et al., 2010). ILK plays a critical role in the suppression of the Hippo pathway in breast, colon and prostate cancer cells; inactivation of ILK suppresses YAP activation and tumour growth in vivo (Serrano et al., 2013c). Expression of LIMD2 is associated with the metastatic process of papillary thyroid carcinoma (Cerutti et al., 2007) and has been described to bound directly to the kinase domain of ILK in IPP, a signal transduction pathway strongly linked to cell motility and invasion suggesting that LIMD2 potentiates ILK biological effects (Peng et al., 2014).
Entity name
Embryonic development
Note
Embryonic lethality was observed in Xenopus laevis (Yasunaga et al., 2005) and mouse (Sakai et al., 2003) models of ILK ablation, and this was attributed to defects in adhesive and migratory mechanics.
Entity name
Musculoskeletal system and skin
Note
During bone formation, ILK-dependent interactions and downstream signaling effectors are required for proliferation and differentiation of chondrocytes within the growth plate. The kinase activity of ILK is necessary for mechanosensing and signaling in vertebrate skeletal muscle (Postel et al., 2008). ILK is important for proliferation, adhesion, spreading and migration of keratinocytes (Lorenz et al., 2007; Nakrieko et al., 2008). ILK plays an important modulatory role in the normal contribution of hair follicle stem cell progeny to the regenerating epidermis following injury (Nakrieko et al., 2011). ILK and PI3K activation after skin wounding are critical for tissue repair in an HGF-dependent mechanism (Serrano et al., 2012).
Disease
Mice with depletion of ILK in chondrocytes suffer from dwarfism and chondrodysplasia (Grashoff et al., 2003; Terpstra et al., 2003). Lack of ILK in skin causes skin blistering and inhibition of hair follicle development (Lorenz et al., 2007; Nakrieko et al., 2008). ILK deficiency in mice leads to retarded wound closure in skin (Serrano et al., 2012).
Entity name
Central nervous system
Note
The downregulation of ILK expression was found to inhibit axon formation through the elimination or length reduction of the axon. ILK-Akt-GSK3 signaling axis is implicated in the development and function of neurons (Guo et al., 2007).
Disease
ILK deletion in the central nervous system leads to Cobblestone lissencephaly (Niewmierzycka et al., 2005) and to cerebellar development and loss of NGF signaling (Mills et al., 2006).
Entity name
Kidney
Note
ILK function is required for epithelial to mesenchymal transition and adhesion and in the maintenance of glomerular filtration barrier. Human mesangial cells exposed to abnormal collagen I are protected against apoptosis by a complex mechanism involving integrin β1/ILK/AKT-dependent NFkB activation with consequent Bcl-xL overexpression, that opposes a simultaneously activated ILK/GSK-3β-dependent Bim expression and this dual mechanism may play a role in the progression of glomerular dysfunction (del Nogal et al., 2012). ILK plays a key role in the regulation of renal inflammation by modulating the canonical NF-kB pathway, and suggest a potential therapeutic target for inflammatory renal diseases (Alique et al., 2014). ILK regulates expression of tubular water channel aquaporin-2 (AQP2) and its apical membrane presence in the renal tubule, polyuria and decreased urine osmolality were present in ILK conditional-knockdown (cKD-ILK) adult mice compared with nondepleted ILK littermates pointing ILK as a therapeutic target in nephrogenic diabetes insipidus (Cano-Penalver et al., 2014).
Disease
Fibrosis; proteinuria (Dai et al., 2006; El-Aouni et al., 2006).
Entity name
Heart
Note
ILK plays a central role in protecting the mammalian heart against cardiomyopathy and failure. Thymosin beta4 activates ILK and promotes cardiac cell function and regeneration after infarction (Bock-Marquette et al., 2004; Srivastava et al., 2007). The heart uses the Integrin-ILK-beta-parvin network to sense mechanical stretch (Bendig et al., 2006). Deletion of ILK results in disaggregation of cardiomyocytes, associated with disruption of adhesion signaling through the beta1-integrin/FAK (focal adhesion kinase) complex (White et al., 2006). ILK is implicated in cardiac hypertrophy and contractility and is a novel cardiotropic factor that promotes recruitment of human fetal heart cells to a cardiomyogenic fate (Traister et al., 2012). Increased expression of integrin-linked kinase improves cardiac function and decreases mortality in dilated cardiomyopathy model of rats (Gu et al., 2012). In Drosophila, severely compromised integrin/ILK pathway function is detrimental for the heart, but fine-tuned moderate reduction maintains youthful cardiac performance, suggesting a dual role for this complex in regulating cardiac integrity and aging (Nishimura et al., 2014).
Disease
Cardiomyogenesis
Entity name
Blood vessels
Note
ILK closely regulates capillary formation and the survival of progenitor and differentiated endothelial cells. In endothelial cells, VEGF stimulates ILK activity, and inhibition of ILK expression or activity results in the inhibition of VEGF-mediated endothelial cell migration, capillary formation in vitro, and angiogenesis in vivo (Tan et al., 2004). ILK controls postnatal vasculogenesis by recruitment of endothelial progenitor cells to ischemic tissue (Lee et al., 2006). ILK acts as a regulatory partner of eNOS in vivo that prevents eNOS uncoupling, and suggest ILK as a therapeutic target for prevention of endothelial dysfunction related to shear stress-induced vascular diseases (Herranz et al., 2012). ILK regulates retinal vascular endothelial proliferation, migration and tube formation and targeting ILK may be a potentially useful therapeutic approach for treating ocular neovascularization (Xie et al., 2013). Deletion of ILK in mice leads to increased vascular content and increased activity of sGC (soluble Guanylyl Cyclase) and PKG (Protein Kinase G), resulting in a more intense vasodilatory response to nitric oxide donors (Serrano et al., 2013a).
Disease
Tumor angiogenesis (Tan et al., 2004).

Article Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 3611
MIM: 602366
HGNC: 6040
Ensembl: ENSG00000166333

Variants:

dbSNP: 3611
ClinVar: 3611
TCGA: ENSG00000166333
COSMIC: ILK

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000166333ENST00000299421Q13418
ENSG00000166333ENST00000299421V9HWF0
ENSG00000166333ENST00000396751Q13418
ENSG00000166333ENST00000396751V9HWF0
ENSG00000166333ENST00000420936Q13418
ENSG00000166333ENST00000420936V9HWF0
ENSG00000166333ENST00000526114E9PQ52
ENSG00000166333ENST00000526318A0A087WWY6
ENSG00000166333ENST00000526711A0A087WW45
ENSG00000166333ENST00000527121E9PQ52
ENSG00000166333ENST00000528995Q13418
ENSG00000166333ENST00000532063Q13418
ENSG00000166333ENST00000537806A0A0A0MTH3
ENSG00000166333ENST00000627400E9PQ52

Expression (GTEx)

0
50
100
150
200
250
300
350
400
450
500

Pathways

PathwaySourceExternal ID
PPAR signaling pathwayKEGGko03320
Axon guidanceKEGGko04360
Focal adhesionKEGGko04510
Endometrial cancerKEGGko05213
PPAR signaling pathwayKEGGhsa03320
Axon guidanceKEGGhsa04360
Focal adhesionKEGGhsa04510
Endometrial cancerKEGGhsa05213
Bacterial invasion of epithelial cellsKEGGko05100
Bacterial invasion of epithelial cellsKEGGhsa05100
Cell-Cell communicationREACTOMER-HSA-1500931
Cell junction organizationREACTOMER-HSA-446728
Cell-extracellular matrix interactionsREACTOMER-HSA-446353
Localization of the PINCH-ILK-PARVIN complex to focal adhesionsREACTOMER-HSA-446343

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
387346962024Integrin-linked kinase mRNA expression in circulating mononuclear cells as a biomarker of kidney and vascular damage in experimental chronic kidney disease.0
387346962024Integrin-linked kinase mRNA expression in circulating mononuclear cells as a biomarker of kidney and vascular damage in experimental chronic kidney disease.0
367329402023Substrate Stiffness Regulates the Proliferation and Apoptosis of Periodontal Ligament Cells through Integrin-Linked Kinase ILK.1
373576862023Extracellular vesicle-packaged ILK from mesothelial cells promotes fibroblast activation in peritoneal fibrosis.6
380773242023Integrin-linked kinase expression in myeloid cells promotes colon tumorigenesis.0
367329402023Substrate Stiffness Regulates the Proliferation and Apoptosis of Periodontal Ligament Cells through Integrin-Linked Kinase ILK.1
373576862023Extracellular vesicle-packaged ILK from mesothelial cells promotes fibroblast activation in peritoneal fibrosis.6
380773242023Integrin-linked kinase expression in myeloid cells promotes colon tumorigenesis.0
349210142022Loss of Integrin-Linked Kinase Sensitizes Breast Cancer to SRC Inhibitors.5
350894382022Integrin-linked kinase (ILK): the known vs. the unknown and perspectives.21
352466162022Indoxyl sulfate- and P-cresol-induced monocyte adhesion and migration is mediated by integrin-linked kinase-dependent podosome formation.9
354299702022Identification and validation of EMT-immune-related prognostic biomarkers CDKN2A, CMTM8 and ILK in colon cancer.15
363598212022The Role of Hippo Signaling Pathway and ILK in the Pathophysiology of Human Hypertrophic Scars and Keloids: An Immunohistochemical Investigation.4
349210142022Loss of Integrin-Linked Kinase Sensitizes Breast Cancer to SRC Inhibitors.5
350894382022Integrin-linked kinase (ILK): the known vs. the unknown and perspectives.21

Citation

Isabel Serrano ; Paul McDonald ; Shoukat Dedhar

ILK (integrin-linked kinase)

Atlas Genet Cytogenet Oncol Haematol. 2014-08-01

Online version: http://atlasgeneticsoncology.org/gene/460/js/css/favicon/manifest.json