TGF?1 Induces Axonal Outgrowth via ALK5/PKA/SMURF1-Mediated Degradation of RhoA and Stabilization of PAR6.

ABSTRACT: Transforming growth factor (TGF)?1 has repeatedly been associated with axonal regeneration and recovery after injury to the CNS. We found TGF?1 upregulated in the stroke-denervated mouse spinal cord after ischemic injury to the motor cortex as early as 4 d postinjury (dpi) and persisting up to 28?dpi. Given the potential role of TGF?1 in structural plasticity and functional recovery after stroke highlighted in several published studies, we investigated its downstream signaling in an in vitro model of neurite outgrowth. We found that in this model, TGF?1 rescues neurite outgrowth under growth inhibitory conditions via the canonical TGF?R2/ALK5 signaling axis. Thereby, protein kinase A (PKA)-mediated phosphorylation of the E3 ubiquitin ligase SMURF1 induces a switch of its substrate preference from PAR6 to the Ras homolog A (RhoA), in this way enhancing outgrowth on the level of the cytoskeleton. This proposed mechanism of TGF?1 signaling could underly the observed increase in structural plasticity after stroke in vivo as suggested by the temporal and spatial expression of TGF?1. In accordance with previous publications, this study corroborates the potential of TGF?1 and associated signaling cascades as a target for future therapeutic interventions to enhance structural plasticity and functional recovery for stroke patients.

SUBMITTER: Kaiser J 

PROVIDER: S-EPMC7540929 | biostudies-literature | 2020 Sep/Oct

REPOSITORIES: biostudies-literature