Src kinase up-regulates the ERK cascade through inactivation of protein phosphatase 2A following cerebral ischemia
- Equal contributors
1 Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 210029, PR China
2 Department of Biochemistry, Nanjing Medical University, Nanjing 210029, PR China
3 Department of General Surgery, The Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing 210006, PR China
4 Laboratory Center for Basic Medical Sciences, Nanjing medical university Nanjing, 210029, PR China
BMC Neuroscience 2009, 10:74 doi:10.1186/1471-2202-10-74Published: 14 July 2009
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.
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 ERα. In addition, the PP2A inhibitor, cantharidin, led to an up-regulation of ERK activity and was able to counteract Src inhibition during ischemia.
Src induces up-regulation of ERK activity and its target transcription factors, CREB and ERα, 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.