Integrin-linked Protein Kinase Regulates Fibronectin Matrix Assembly, E-cadherin Expression, and Tumorigenicity

Wu, Chuanyue; Keightley, Sarah Y.; Leung-Hagesteijn, Chungyee; Radeva, Galena; Coppolino, Marc G.; Goicoechea, Silvia M.; McDonald, John A.; Dedhar, Shoukat

doi:10.1074/jbc.273.1.528

Cited by 269 publications

(235 citation statements)

References 72 publications

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“…Cell survival and cell growth regulated by growth factor signalling (Moustakas et al, 2002;Neve et al, 2002) have been shown by Wu et al (1998) to be also substantially affected by ILK signalling upon ligand binding to b1-integrin receptors. The ILK signalling cascade seems to be involved in tumour growth, tumorigenesis and in the development of a metastatic phenotype.…”

Section: Discussionmentioning

confidence: 99%

Cell adhesion to the extracellular matrix protein fibronectin modulates radiation-dependent G2 phase arrest involving integrin-linked kinase (ILK) and glycogen synthase kinase-3β (GSK-3β) in vitro

Cordes

Beuningen

2003

Br J Cancer

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Cell adhesion to extracellular matrix (ECM) is thought to confer resistance against cell-damaging agents, that is, drugs and radiation, in tumour and normal cells in vitro. The dependence of cell survival on b1-integrin-linked kinase (ILK), protein kinase Ba/Akt (PKBa/Akt) and glycogen synthase kinase-3b (GSK-3b) activity, which participate in b1-integrin signalling and cell cycle progression was investigated as a function of radiation exposure. Colony-formation assays on polystyrene, fibronectin (FN), laminin (LA), bovine serum albumin (BSA) or poly-L-lysine (poly-L) (0 -8 Gy), kinase assays, flow cytometric DNA and annexin-V analysis and immunoblotting were performed in nonirradiated and irradiated (2 or 6 Gy) A549 human lung cancer cells and CCD32 normal human lung fibroblasts. Cell contact to FN in contrast to polystyrene elevated basal ILK, PKBa/Akt and GSK-3b kinase activities in A549 and CCD32 cells, as well as the basal amount of A549 G2 phase cells. Irradiation on FN or LA as compared to polystyrene, BSA or poly-L significantly improved cell survival. Following irradiation, kinase activities were stimulated strongly on polystyrene but showed to be less prominent on FN, which was because of the FN-related basal induction. Following irradiation, FN compared to polystyrene enlarged and prolonged G2 arrest in both the cell lines. For the analysis of phosphatidylinositol-3 kinase (PI3-K) dependence of protein kinases and cell cycle transition, the PI3-K inhibitors LY294002 and wortmannin were used showing decreased kinase activities, antiproliferative and radiation-dependent G2 accumulation-abrogating effects accompanied by downregulation of cyclin D1 and phospho-pRb in cells attached to polystyrene. Fibronectin partly abrogated these effects PI3-Kindependently. These findings suggest a novel pathway that makes direct phosphorylation of GSK-3b by ILK feasible after irradiation. Conclusively, the data indicate that ILK, PKBa/Akt and GSK-3b are involved in modulations of the cell cycle after irradiation. These interactions are strictly dependent on ECM components in a cell line-specific manner. Our findings provide molecular insights into mechanisms likely to be important for ECM-dependent cell survival and cellular radioresistance as well as tumour growth.

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Section: Discussionmentioning

confidence: 99%

Cell adhesion to the extracellular matrix protein fibronectin modulates radiation-dependent G2 phase arrest involving integrin-linked kinase (ILK) and glycogen synthase kinase-3β (GSK-3β) in vitro

Cordes

Beuningen

2003

Br J Cancer

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“…This relation may be a direct effect from tumor to normal adjacent cells, a secondary effect because of specific characteristics conferred on the tumor by SNAI1 expression or related to other unknown alterations. For example, changes in secreted matrix proteins by tumor cells could modulate the expression of CDH1 in adjacent cells through the activation of the integrin-linked kinase (Lochter et al, 1997;Wu et al, 1998;Menke et al, 2001). This effect might be mediated by SNAI1 activation in adjacent cells, as SNAI1 transcription is stimulated by integrinlinked kinase activation in colon cells (Tan et al, 2001).…”

Section: Adh-gfp Adh-sn Row Column Cytokine Cytokinefull Name Median mentioning

confidence: 99%

SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue

et al. 2009

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SNAI1, ZEB1, E-cadherin (CDH1), and vitamin D receptor (VDR) genes regulate the epithelial-mesenchymal transition (EMT) that initiates the invasion process of many tumor cells. We hypothesized that this process could also affect the behavior of normal cells adjacent to the tumor. To verify this hypothesis, the expression level of these genes was determined by quantitative RT-PCR in tumor, normal adjacent, and normal distant tissues from 32 colorectal cancer (CC) patients. In addition, we extended the study to human HaCaT normal keratinocytes and SW480-ADH colon cancer cells co-cultured with SW480-ADH cells overexpressing the mouse Snai1 gene. Of 18 CC cases with SNAI1 expression in tumor tissue, five also had SNAI1 in normal adjacent tissue (NAT). Expression of SNAI1 in tumor tissue correlated with downregulation of CDH1 and VDR genes in both tumor (P ¼ 0.047 and P ¼ 0.014, respectively) and NAT lacking SNAI1 expression (P ¼ 0.054 and P ¼ 0.003). ZEB1 expression was directly related to VDR expression in tumor tissue (r ¼ 0.39; P ¼ 0.027) and inversely to CDH1 in NAT (r ¼ À0.46; P ¼ 0.010). CDH1 and VDR were also downregulated in SW480-ADH and MaCaT cells, respectively, when they were co-cultured with Snai1-expressing cells. Furthermore, cytokine analysis showed differences in the conditioned media obtained from the two cell types. These results indicate that histologically normal tissue adjacent to tumor tissue expressing the EMT-inducing gene SNAI1 shows alterations in the expression of epithelial differentiation genes such as CDH1 and VDR.

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“…Overexpression of ILK in normal epithelial cells (Scp2 mouse mammary epithelial cells and IEC-18 rat intestinal epithelial cells) results in anchorageindependent growth, 36 cell-cycle progression 37 and tumorigenicity in nude mice. 38 The apparent contradiction between these 2 models may be due to the cellular context in which ILK was expressed. Normal epithelial cells express optimal levels of ILK, whereas the MDA-MB-435 cells have sub-threshold ILK expression.…”

Section: Growth-inhibitory Functions Of Ilkmentioning

confidence: 99%

“…This in turn induces anchorage-independent growth, 36 cell-cycle progression 37 and tumorigenicity in nude mice. 38 Clearly, the functions of ILK are more complex than previously envisioned, and the divergent and often paradoxical effects mediated by ILK may depend on the particular cell type, cell environment and the cell-specific integrins that are activated.…”

Section: Growth-inhibitory Functions Of Ilkmentioning

confidence: 99%

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

Chen

Shen

Karnik

2004

Intl Journal of Cancer

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Allelic loss at the short arm of chromosome 11 is one of the most common and potent events in the progression and metastasis of breast cancer. Here, we present evidence that the Integrin-Linked Kinase (ILK) gene maps to the commonly deleted chromosome 11p15. Genetic alterations that occur in breast cancer are believed to be of importance for initiation as well as progression of the disease. These genetic alterations lead to the loss or activation of a number of critical genes, such as those involved in cell proliferation, differentiation, apoptosis and genetic stability. The genetic abnormalities most frequently observed in breast tumors are amplification of proto-oncogenes (MYC, ERBB2 and CCND1), mutations of TP53 and loss of heterozygosity (LOH) on chromosomes 3p, 6q, 7q, 8p, 9p, 11, 13q, 17, 18q and 22q. 1,2 Metastatic phenotypes have been linked to such genes as NME1 (17q), CDH1 (16q), BRMS1 (11q) and KISS1 (1q). 1,3-5 LOH analyses have defined regions of deletion associated with metastasis on chromosomes 3p21, 15q14, 16q22 and 11p15. 2,6 Frequent genetic alterations on chromosome 11p15 suggest a crucial role for this region in breast 6,7 and other adult 8 -12 and childhood cancers. [13][14][15][16][17] More recently, we have mapped 2 distinct regions on chromosome 11p15.5 that are subject to LOH during breast tumor progression and metastasis. 6 LOH at region 1 correlated with tumors that contain ductal carcinoma in situ, suggesting that the loss of a critical gene in this region may be responsible for early events in malignancy. LOH at region 2 correlated with a more aggressive tumor and an ominous outlook for the patient, such as aneuploidy, high S-phase fraction and the presence of metastasis in regional lymph nodes. Although considerable advances have been made in the fine-mapping of chromosome 11p15.5, the tumor/metastasis suppressor gene(s) encoded by this region has evaded identification.Integrin-linked kinase (ILK) is an intriguing serine/threonine kinase that has been implicated in integrin-, growth-factor-and Wnt-signaling pathways. 18 It binds to the cytoplasmic domains of ␤1 and ␤3 integrins and mediates the downstream signaling events in integrin function. 19 Interactions between integrins and their ligands are involved in the regulation of many cellular functions, including embryonic development, cell proliferation, tumor growth and the ability to metastasize. 20 In Drosophila, the absence of ILK function causes defects similar to loss of integrin adhesion, and ILK mutations cause embryonic lethality and defects in muscle attachment. 21 Although ILK maps to the commonly deleted chromosome 11p, the potential of this gene in tumor/metastasis suppression has not been evaluated. We have therefore analyzed the effect of ILK expression on the in vitro and in vivo tumor growth and invasion of human mammary carcinoma cells. MATERIAL AND METHODS Mapping of ILK to LOH region 2Two YAC clones (847a12 and 696H10), a BAC clone (BAC 1760) and a PAC clone (PAC1331) overlapped the LOH region 2 and were used to...

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Integrin-linked Protein Kinase Regulates Fibronectin Matrix Assembly, E-cadherin Expression, and Tumorigenicity

Cited by 269 publications

References 72 publications

Cell adhesion to the extracellular matrix protein fibronectin modulates radiation-dependent G2 phase arrest involving integrin-linked kinase (ILK) and glycogen synthase kinase-3β (GSK-3β) in vitro

Cell adhesion to the extracellular matrix protein fibronectin modulates radiation-dependent G2 phase arrest involving integrin-linked kinase (ILK) and glycogen synthase kinase-3β (GSK-3β) in vitro

SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

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