Protein Kinase CK2/PTEN Pathway Plays a Key Role in Platelet-Activating Factor-Mediated Murine Anaphylactic Shock

Abstract

Platelet-activating factor (PAF) is a major mediator in the induction of fatal hypovolemic shock in murine anaphylaxis. This PAF-mediated effect has been reported to be associated with PI3K/Akt-dependent eNOS-derived NO. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is phosphatidylinositol phosphate phosphatase, which negatively controls PI3K by dephosphorylating the signaling lipid, phosphatidylinositol 3,4,5-triphosphate. In this study, we examined the possible involvement of PTEN in PAF-mediated anaphylactic shock. Induction of anaphylaxis or PAF injection resulted in a rapid decrease in PTEN activity, followed by increases in PI3K activity and phosphorylation of Akt and eNOS. Systemic administration of adenoviruses carrying PTEN cDNA (adenoviral PTEN), but not the control AdLacZ, not only attenuated anaphylactic symptoms, but also reversed anaphylaxis- or PAF-induced changes in PTEN and PI3K activities, as well as phosphorylation of Akt and eNOS. We found that the decreased PTEN activity was associated with PTEN phosphorylation, the latter effect being prevented by the protein kinase CK2 inhibitor, DMAT. DMAT also inhibited anaphylactic symptoms as well as the anaphylaxis- or PAF-mediated PTEN/PI3K/Akt/eNOS signaling cascade. CK2 activity was increased by PAF. The present data provide, as the key mechanism underlying anaphylactic shock, PAF triggers the upstream pathway CK2/PTEN, which ultimately leads to the activation of PI3K/Akt/eNOS. Therefore, CK2/PTEN may be a potent target in the control of anaphylaxis and other many PAF-mediated pathologic conditions.

Platelet‐activating factor enhances tumour metastasis via the reactive oxygen species‐dependent protein kinase casein kinase 2‐mediated nuclear factor‐κB activation

“…Many signals, such as LPS, TNF‐ α , interleukin‐1, transforming growth factor‐ β and interferon‐ γ have been found to enhance the constitutive activity of CK2 . In the present study, we confirmed the results of our previous study, showing that PAF enhances CK2 activity . Additionally, we further demonstrated that PAF enhanced CK2 α phosphorylation and its protein expression.…”

“…Regarding the molecular mechanism underlying the regulation of CK2, we have recently reported that PAF increases the enzymatic activity of CK2 in vivo . This suggests the possibility that CK2 is involved in biological roles of PAF.…”

Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis

“…Of note, increased E2F1 leads to p53-dependant repression of VE 40,41 , which normally destabilizes VE-cadherin junctions 19 , which may also contribute to this phenotype. This observation is supported by the fact that E2F1 knockout mice have increased vascular permeability, rapid PTEN reduction is seen during anaphylaxis, and that PTEN-deficient mice have enhanced allergic responses and increased vascular permeability 40,42–44 . While the link between STAT3, the miR17–92 complex, PTEN expression and SRC-mediated responsiveness to histamine appears intriguing, further work will be necessary to definitively describe this mechanism.…”

PTEN/MAPK pathways play a key role in platelet‐activating factor‐induced experimental pulmonary tumor metastasis

“…We showed that the decreased PTEN activity played a role in the tumor metastasis by demonstrating that systemic administration of Ad‐PTEN not only restored PAF‐induced reduction in PTEN activity but also inhibited PAF‐induced tumor metastasis. We previously showed that PAF induced decrease in PTEN activity plays a key role in the induction of anaphylaxis [29]. Therefore, PTEN involvement seems to be a central mechanism underlying the biological actions of PAF.…”