Phosphorylation is a highly abundant, effective and reversible means of initiating and mediating signaling pathways in the brain. Therefore, the proteins and transcription factors undergoing phosphorylation-mediated alterations after traumatic brain injury (TBI) represent therapeutic targets with high potential to reverse signaling pathways that propagate cell death and dysfunction after traumatic brain injury (TBI). A main initiator of these TBI-induced signaling pathways is the excitotoxic increase in glutamate in the brain and subsequent activation of glutamatergic receptors and calcium influx into neurons. As therapies for TBI that broadly inhibit glutamate receptors have proven unsuccessful in the clinic, the need for more specific therapeutic targets downstream of glutamate receptor activation is great. Identifying and characterizing phosphorylationdriven signaling after trauma represents an ideal way to identify these potential targets in TBI.

Therefore, we identified two proteins that are mediated by and that drive phosphorylation changes under conditions of trauma. We first examined alterations in the phosphorylation and proteolysis of striatal enriched tyrosine phosphatase (STEP) after in vitro and in vivo mechanical stretch injury, in addition to chemical stimulation. We found that STEP activity and expression can be drastically altered depending on the timing, severity of injury and mechanism of injury and that the formation of a calpainmediated cleavage product of STEP correlates well with cell death after injury. The injury-induced STEP alterations occur through signaling via the NMDA receptor, yet the nature and timing of the stimulus determines whether STEP is activated or inactivated post-injury. We also found that increased extranuclear phosphorylation of the transcription factor Elk-1 on a potentially neurotoxic residue is conserved across multiple models of injury and correlates well with apoptotic cell death after injury. Together, our findings provide key insights into the effect of mechanical stretch injury on both STEP and Elk-1 and highlight their potential for further study as therapeutic targets in TBI.