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Abstract
BackgroundIncreased activity or expression of integrin-linked kinase (ILK), which regulates cell adhesion, migration, and proliferation, leads to oncogenesis. We identified the molecular basis for the regulation of ILK and its alternative role in conferring ERK1/2/NF-κB-mediated growth advantages to gastric cancer cells.ResultsInhibiting ILK with short hairpin RNA or T315, a putative ILK inhibitor, abolished NF-κB-mediated the growth in the human gastric cancer cells AGS, SNU-1, MKN45, and GES-1. ILK stimulated Ras activity to activate the c-Raf/MEK1/2/ERK1/2/ribosomal S6 kinase/inhibitor of κBα/NF-κB signaling by facilitating the formation of the IQ motif-containing GTPase-activating protein 1 (IQGAP1)–Ras complex. Forced enzymatic ILK expression promoted cell growth by facilitating ERK1/2/NF-κB signaling. PI3K activation or decreased PTEN expression prolonged ERK1/2 activation by protecting ILK from proteasome-mediated degradation. C-terminus of heat shock cognate 70 interacting protein, an HSP90-associated E3 ubiquitin ligase, mediated ILK ubiquitination to control PI3K- and HSP90-regulated ILK stabilization and signaling. In addition to cell growth, the identified pathway promoted cell migration and reduced the sensitivity of gastric cancer cells to the anticancer agents 5-fluorouracil and cisplatin. Additionally, exogenous administration of EGF as well as overexpression of EGFR triggered ILK- and IQGAP1-regulated ERK1/2/NF-κB activation, cell growth, and migration.ConclusionAn increase in ILK non-canonically promotes ERK1/2/NF-κB activation and leads to the growth of gastric cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-014-0069-3) contains supplementary material, which is available to authorized users.
Highlights
Increased activity or expression of integrin-linked kinase (ILK), which regulates cell adhesion, migration, and proliferation, leads to oncogenesis
To investigate the possible mechanisms underlying ILKmediated gastric cancer cell growth, several gastric epithelial cell lines were characterized according to their different cell growth rates, which were higher for the AGS and SNU-1 cells and lower for the MKN45 and GES-1 cells, and used in this study (Additional file 3: Figure S2A)
ILK overexpression was accompanied by ERK1/2 and AKT activation; inhibiting phosphatidylinositol 3-kinase (PI3K) and HSP90 decreased ILK expression and ERK1/2 and AKT activation (Figure 7E). These findings demonstrated that both ILK and IQ motif-containing GTPase-activating protein 1 (IQGAP1) are required for EGF/EGFR-triggered ERK1/2/NF-κB activation and cell growth advantages and that ILK expression can be positively regulated by EGF/EGFR/PI3K/HSP90 signaling
Summary
Increased activity or expression of integrin-linked kinase (ILK), which regulates cell adhesion, migration, and proliferation, leads to oncogenesis. ILK comprises three domains: N-terminal ankyrin (ANK) repeats, a central pleckstrin homology (PH)-like domain, and a C-terminal kinase domain [2,3]. After ILK activation, the Cterminal kinase domain of ILK can bind to various proteins, including AKT, affixin, β-parvin, glycogen synthase kinase (GSK)-3β, calponin homology-containing ILKbinding protein, the 20-kDa regulatory light chains of myosin (LC20), the myosin-targeting subunit of myosin light chain phosphatase (MYPT1), paxillin, α-NAC, and the protein phosphatase inhibitors PHI-1, KEPI, and CPI-17 [2,3,6,7]. The N-terminal ANK repeats mediate the interaction of ILK with ILKAP, a protein phosphatase 2C family member, and PINCH, an LIM domain-only adaptor protein. ILK can be considered a PIP3-interacting protein downstream of PI3K; its effects are blocked by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) [8,9]. PTEN suppresses tumors by dephosphorylating PIP3 [10,11]
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