Neisseria gonorrhoeae-induced transactivation of EGFR enhances gonococcal invasion

Swanson, Karen V.; Griffiss, J. McLeod; Edwards, Vonetta L.; Stein, Daniel C.; Song, Wenxia

doi:10.1111/j.1462-5822.2011.01603.x

Cited by 28 publications

(54 citation statements)

References 36 publications

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“…We determined three specific sites on EGFR, ErbB2, and ErbB4 that are phosphorylated in response to meningococcal infection, including Tyr845 of EGFR, Thr686 of ErbB2, and Tyr1284 of ErbB4. Moreover, we determined that the mechanism underlying the activation of EGFR and ErbB4 receptor phosphorylation involves activation of the common receptor ligand HB-EGF, as recently demonstrated for the related species N. gonorrhoeae (34). Furthermore, EGFR phosphorylation at Tyr845 occurrs downstream of c-Src.…”

Section: Discussionmentioning

confidence: 66%

“…Moreover, ErbB2 phosphorylation has been demonstrated to be involved in meningococcal uptake by endothelial cells (11). Through induction of ErbB2 receptor phosphorylation, N. meningitidis is capable of activating c-Src and cortactin, which links the host cell cytoskeleton to host cell membrane receptors (10,11,34,36).…”

Section: Discussionmentioning

confidence: 99%

“…We therefore hypothesized that ErbB activation is mediated by transactivation via activation of endogenous ligands, as described for H. pylori and the related species N. gonorrhoeae (34,44). Phosphorylation of EGFR mediated through release of HB-EGF has also been observed after incubation of epithelial cells with Gram-positive lipoteichoic acid (44,55).…”

Section: Discussionmentioning

confidence: 99%

“…Since the neutralizing antibodies interfered with the binding sites for growth factors, we hypothesized that N. meningitidis might transactivate EGFR and ErbB4 via activation of endogenous ligands, as described for H. pylori and the related species N. gonorrhoeae (34,44), supporting bacterial uptake. Numerous ligands are known to cause transactivation of the EGFR family, and pre- vious studies have shown that EGFR transactivation could be linked to cleavage of the membrane-bound pro-heparin-binding EGF-like growth factor (pro-HB-EGF) that activates EGFR in a number of systems (45).…”

Section: Fig 4 N Meningitidis Internalization By Hbmec Requires Erbbmentioning

confidence: 99%

“…The related species Neisseria gonorrhoeae has been shown to induce accumulation of both EGFR and ErbB2 at the site of bacterial attachment. Activation of EGFR is mediated through HB-EGF ectodomain shedding and is involved in uptake of N. gonorrhoeae by epithelial cells (34).…”

mentioning

confidence: 99%

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Role of Epidermal Growth Factor Receptor Signaling in the Interaction of Neisseria meningitidis with Endothelial Cells

et al. 2014

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Neisseria meningitidis, the causative agent of meningitis and septicemia, attaches to and invades various cell types. Both steps induce and/or require tyrosine phosphorylation of host cell proteins. Here, we used a phospho array platform to identify active receptor tyrosine kinases (RTKs) and key signaling nodes in N. meningitidis-infected brain endothelial cells to decipher RTKdependent signaling pathways necessary for bacterial uptake. We detected several activated RTKs, including the ErbB family receptors epidermal growth factor receptor (EGFR), ErbB2, and ErbB4. We found that pharmacological inhibition and genetic ablation of ErbB receptor tyrosine phosphorylation and expression resulted in decreased bacterial uptake and heterologous expression of EGFR, ErbB2, or ErbB4 in Chinese ovary hamster (CHO-K1) cells, which do not express of EGFR and ErbB4; the decrease caused a significant increase in meningococcal invasion. Activation of EGFR and ErbB4 was mediated by transactivation via the common ligand HB-EGF (heparin-binding EGF-like ligand), which was significantly elevated in infected cell culture supernatants. We furthermore determined that N. meningitidis induced phosphorylation of EGFR at Tyr845 independent of ligand binding, which required c-Src activation and was involved in mediating uptake of N. meningitidis into eukaryotic cells. Increased uptake was repressed by expression of EGFR Y845F, which harbored a point mutation in the kinase domain. In addition, activation of ErbB4 at its autophosphorylation site, Tyr1284, and phosphorylation of ErbB2 Thr686 were observed. Altogether, our results provide evidence that EGFR, ErbB2, and ErbB4 are activated in response to N. meningitidis infection and shed new light on the role of ErbB signaling in meningococcal infection biology. N eisseria meningitidis is a common colonizing bacterium of the human nasopharynx and can be found in 8 to 20% of healthy individuals (1). In rare cases, N. meningitidis overcomes the epithelial barrier and enters the bloodstream, followed by a severe septicemia or by an acute purulent meningitis (2). To cross cellular barriers, N. meningitidis has evolved with the ability to attach to and invade into a variety of cell types. N. meningitidis interacts with host cells by using several microbial structures, including type IV pili (TfP), the outer membrane adhesion proteins Opa and Opc, and the newly identified minor adhesion or adhesion-like proteins that mediate binding to different receptors (3-8). Subsequently, binding to receptors enables the pathogen to exploit the endocytotic capacity of the receptor to promote its internalization. In addition to the engagement of a specific receptor, microorganisms might indirectly activate signal transduction pathways and co-opt receptor signal transduction mechanisms to induce host cell signaling pathways that in turn lead to cytoskeleton rearrangements and bacterial uptake.It has been established that N. meningitidis can signal through receptor tyrosine kinases (RTKs) and non-RTKs to promote th...

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Section: Discussionmentioning

confidence: 66%