Src kinase up-regulates the ERK cascade through inactivation of protein phosphatase 2A following cerebral ischemia

Background: The regulation of protein phosphorylation requires a balance in the activity of protein kinases and protein phosphatases. Our previous data indicates that Src can increase ERK activity through Raf kinase in response to ischemic stimuli. This study examined the molecular mechanisms by which Src activates ERK cascade through protein phosphatases following cerebral ischemia. Results: Ischemia-induced Src activation is followed by phosphorylation of PP2A at Tyr307 leading to its inhibition in the rat hippocampus. SU6656, a Src inhibitor, up-regulates PP2A activity, resulting in a significant decreased activity in ERK and its targets, CREB and ER alpha. In addition, the PP2A inhibitor, cantharidin, led to an up-regulation of ERK activity and was able to counteract Src inhibition during ischemia. Conclusion: Src induces up-regulation of ERK activity and its target transcription factors, CREB and ERa, through attenuation of PP2A activity. Therefore, activation of ERK is the result of a crosstalk between two pathways, Raf-dependent positive regulators and PP2A-dependent negative regulators.