In this study, we found that sPLA2 IIA induced a phenotype of act

In this study, we found that sPLA2 IIA induced a phenotype of activated microglia in BV 2 cells which is linked to the activation of the clas sical MAPK ERK and mTOR selleck P70S6K pathways through MMP dependent ectodomain shedding of the transmem brane precursor pro HB EGF and subsequent transacti vation of the EGFR. The Inhibitors,Modulators,Libraries EGFR is expressed ubiquitously in the mammalian brain, being detected in neurons and glia cells. It has been hypothesized that EGFR activation is a master signal transduction pathway of the cellular activation process in response to different brain injuries and causes the characteristics of the reactive astrocyte microglia phenotype. Thus, activation of the EGFR path way is responsible for the hypertrophy, proliferation and migration of reactive astrocytes, and perhaps of activated microglia, at the site of neural injury.

We Inhibitors,Modulators,Libraries have herein showed that sPLA2 IIA induces a sustained EGFR phosphorylation at Tyr 1176 and Tyr 845 residues that is abolished or diminished in the presence of the selective EGFR inhibitor, AG1478. To understand the mechanisms by which phospholipase causes EGFR phos phorylation, we used a general matrix metalloprotease inhibitor and an ADAMs inhibitor, which are known to block the proteolytic cleavage of various membrane anchored EGFR pro ligands such as pro EGF, pro TGF, pro HB EGF, and pro amphiregulin. We have found that the presence of these inhibitors blocked the effect of sPLA2 IIA on EGFR phosphorylation as well as on ectodomain shedding of HB EGF, suggesting a possible role of ADAMs and HB EGF in sPLA2 IIA induced EGFR transactivation.

Although it Inhibitors,Modulators,Libraries is possible that other EGFR ligands could be also involved in sPLA2 IIA induced EGFR transactivation, the fact that the presence of a HB EGF neutralizing Ab prevented the molecular and biological effects of the phospholipase suggests that HB EGF plays a major role in the Inhibitors,Modulators,Libraries response induced by the sPLA2 IIA. We focused mainly on HB EGF because of the extensive literature showing its role Inhibitors,Modulators,Libraries in cell survival and proliferation, both in vivo and in vitro. Whether the remnant C terminal fragment generated, HB EGF CTF, translocates to the nucleus and plays any role in sPLA2 IIA signaling should be investigated in greater detail in the future. Interestingly, transactivation of EGFR upon microglial stimulation with IFN�� also involves HB EGF shedding, and is critical for the mito genic and pro inflammatory activity of this cytokine.

This cross talk mechanism between different signaling systems allows the integration of the great diversity of stimuli and supports the key role of the EGFR in diverse pathophysio logical disorders. Additionally, we showed that sPLA2 IIA induces rapid phosphorylation on Src at Tyr 416, and by using than the selective inhibitor PP2 we demonstrated that Src partici pates in both HB EGF shedding and EGFR phosphoryl ation at Tyr 845 and at Tyr 1173.

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