Integrin-linked kinase is an essential link between integrins and uptake of bacterial pathogens by epithelial cells

Wang, Beinan; Yurecko, Ryan S.; Dedhar, Shoukat; Cleary, P. Patrick

doi:10.1111/j.1462-5822.2005.00618.x

Cited by 70 publications

(78 citation statements)

References 44 publications

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“…In this context, it is notable that mRNA of the ILK was up-regulated in infected HBMEC in response to both meningococcal isolates. ILK was recently described to act as an essential link between integrins and the uptake of group A streptococci into epithelial cells (63). In the present study, it now becomes evident that there is also increased transcriptional activity of negative regulators of the MAPK signaling pathways.…”

Section: Discussionsupporting

confidence: 61%

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

et al. 2007

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To extend our knowledge of target proteins in endothelial cells infected with the meningitis-causing pathogen Neisseria meningitidis, we characterized the interaction between the bacterial and human brain microvascular endothelial cell (HBMEC) monolayers. By use of human cDNA microarrays, transcriptional analysis revealed distinct responses to 4 and 8 h of infection. We also addressed the question of whether the major virulence factor of meningococci, i.e., the capsule, influences the host cell response. Of the 1,493 (at 4 h postinfection) and 1,246 (at 8 h postinfection) genes with altered expression upon bacterial contact, about 49.4% and 45%, respectively, depended on capsule expression. In particular, we identified an increase of expression for genes encoding proteins involved in bacterial adhesion and invasion. High levels of apoptosis-related gene (bad, bak, asp, and immediate-early response gene 1) expression could also be detected in infected cells. Further analyses confirmed that HBMECs displayed several hallmarks of apoptosis in response to N. meningitidis infection, namely, phosphatidylserine translocation and activation of caspase 3 and AMP-activated protein kinase ␣. Moreover, several differentially regulated genes not previously known to respond to meningococcal infection were identified. Of these, genes encoding cell adhesion proteins (CD44, CD98, and CD99), genes involved in downstream signaling of integrins (integrin-linked kinase, mitogen-activated protein kinase kinase 1, and mitogen-activated protein kinase kinase kinase 10) as well as negative regulators of these pathways (dualspecificity phosphatases 1, 5, and 14 and G protein pathway suppressor 2), and genes involved in cytoskeleton reorganization (those encoding Arp2/3, p34-arc, actinin alpha 1, vasodilatator-stimulated protein, and Wiskott-Aldrich syndrome protein) were the most prominent. This global transcriptional analysis creates a new platform for further molecular and cellular analysis of the interaction between N. meningitidis and target cells.

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Section: Discussionsupporting

confidence: 61%

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

et al. 2007

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“…The prtF1 gene was introduced into strain M1 Ϫ 90-226 to generate a M1 Ϫ PrtF1 ϩ recombinant of strain 90-226. This recombinant regained the potential to invade epithelial cells efficiently in the presence of exogenous Fn (10). Invasion assays showed that expression of PrtF1 protein by strain M1 Ϫ 90-226 resulted in greater uptake of bacteria by TGF-␤1-treated epithelial cells without an exogenous source of Fn (Fig.…”

Section: Tgf-␤1 Enhanced Invasion Depends On Fn-binding Proteins Of Gasmentioning

confidence: 99%

“…Our previous findings demonstrated that inactivation of integrin signaling signif-icantly inhibited GAS invasion (10,12). TGF-␤1 is known to up-regulate integrin signaling and expression of ECM proteins; therefore, we postulated that TGF-␤1 could enhance GAS invasion.…”

Section: Tgf-␤1 Enhances Gas Invasion Of Epithelial Cellsmentioning

confidence: 99%

“…TGF-␤1 was shown to increase adherence to and invasion of brain microvascular endothelial cells by Escherichia coli K1; however, the molecular basis for this change was not further explored (25). Recent studies on the involvement of integrin signaling associated with GAS invasion prompted us to postulate that exposure of epithelial cells to TGF-␤1 would increase their capacity to ingest GAS (10). This hypothesis was tested with HEp-2 cells and primary human tonsil fibroblasts (PHTF).…”

mentioning

confidence: 99%

“…The bacteria can express several invasins, but the Fn-binding proteins (FnBPs), M1 and PrtF1͞Sfb1, have been studied in most detail (9)(10)(11). Engagement of ␣5␤1 integrin with Fn bound to these proteins initiates phosphoinositide 3-kinase (10,12) and integrin-linked kinase-dependent intracellular signals that induce cytoskeletal rearrangement and ingestion of streptococci (10). Most studies of invasion have used immortalized human cell lines; however, a connection between ␣5␤1 integrin and Fn was also confirmed when GAS invasion was studied in primary cultures of human tonsillar cells (8).…”

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confidence: 99%

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Streptococcal modulation of cellular invasion via TGF-β1 signaling

Wang

Southern

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Group A Streptococcus (GAS) and other bacterial pathogens are known to interact with integrins as an initial step in a complex pathway of bacterial ingestion by host cells. Efficient GAS invasion depends on the interaction of bound fibronectin (Fn) with integrins and activation of integrin signaling. TGF-␤1 regulates expression of integrins, Fn, and other extracellular matrix proteins, and positively controls the integrin signaling pathway. Therefore, we postulated that TGF-␤1 levels could influence streptococcal invasion of mammalian cells. Pretreatment of HEp-2 cells with TGF-␤1 increased their capacity to ingest GAS when the bacteria expressed fibronectin-binding proteins (M1 or PrtF1). Western blots revealed significant induction of ␣5 integrin and Fn expression by HEp-2 cells in response to TGF-␤1. Increased ingestion of streptococci by these cells was blocked by a specific inhibitor of the TGF-␤1 receptor I and antibodies directed against ␣5 integrin and Fn, indicating that increased invasion depends on TGF-␤1 up-regulation of both the ␣5 integrin and Fn. The capacity of TGF-␤1 to up-regulate integrin expression and intracellular invasion by GAS was reproduced in primary human tonsil fibroblasts, which could be a source of TGF-␤1 in chronically infected tonsils. The relationship between TGF-␤1 and GAS invasion was strengthened by the observation that TGF-␤1 production was stimulated in GASinfected primary human tonsil fibroblasts. These findings suggest a mechanism by which GAS induce a cascade of changes in mammalian tissue leading to elevated expression of the ␣5␤1 receptor, enhanced invasion, and increased opportunity for survival and persistence in their human host.integrin ͉ fibronectin ͉ fibronectin binding protein ͉ tonsils

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Validation and simplification of a score predicting survival in patients irradiated for metastatic spinal cord compression

Rades

Douglas

Veninga

et al. 2010

Cancer

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BACKGROUND:Based on an analysis of 1852 retrospectively evaluated patients with metastatic spinal cord compression (MSCC), a scoring system was developed to predict survival. This study was performed to validate the scoring system in a new data set. METHODS: The score included 6 prognostic factors: tumor type, interval between tumor diagnosis and MSCC, other bone or visceral metastases, ambulatory status, and duration of motor deficits. Scores ranged between 20 and 45 points, and patients were initially divided into 5 groups: those with 20 to 25 points, those with 26 to 30 points, those with 31 to 35 points, those with 36 to 40 points, and those with 41 to 45 points. To facilitate the clinical use of the score, the patients were regrouped into 3 groups: those with 20 to 30 points, those with 31 to 35 points, and those with 36 to 45 points. In this study, data of 439 new patients were included who were divided into the same prognostic groups as in the preceding study. RESULTS: In this study, the 6-month survival rates were 7% (for those with 20-25 points), 19% (for those with 26-30 points), 56% (for those with 31-35 points), 73% (for those with 36-40 points), and 90% (for those with 41-45 points), respectively (P <.0001). After regrouping, the 6-month survival rates were 14% (for those with 20-30 points), 56% (for those with 31-35 points), and 80% (for those with 36-45 points), respectively, in this study (P <.0001). CONCLUSIONS: In the current study, the difference in 6-month survival between the prognostic groups was found to be as significant as in the preceding study. Thus, this scoring system was considered valid to estimate survival of MSCC patients. The system could have been simplified by including only 3 instead of 5 prognostic groups. Cancer 2010;116;3670-3.

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Integrin-linked kinase is an essential link between integrins and uptake of bacterial pathogens by epithelial cells

Cited by 70 publications

References 44 publications

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

Streptococcal modulation of cellular invasion via TGF-β1 signaling

Validation and simplification of a score predicting survival in patients irradiated for metastatic spinal cord compression

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