Neuronal apoptosis induced by selective inhibition of Rac GTPase versus global suppression of Rho family GTPases is mediated by alterations in distinct mitogen-activated protein kinase signaling cascades [Signal Transduction]

February 9th, 2015 by Stankiewicz, T. R., Ramaswami, S. A., Bouchard, R. J., Aktories, K., Linseman, D. A.

Rho family GTPases play integral roles in neuronal differentiation and survival. We have previously shown that Clostridium difficile toxin B (ToxB), an inhibitor of RhoA, Rac1, and Cdc42, induces apoptosis of cerebellar granule neurons (CGNs). In the current study, we compared the effects of ToxB to a selective inhibitor of the Rac-specific guanine nucleotide exchange factors (GEFs), Tiam1 and Trio (NSC23766). In a manner similar to ToxB, selective inhibition of Rac induces CGN apoptosis that is associated with enhanced caspase-3 activation and reduced phosphorylation of the Rac effector, p21-activated kinase (PAK). In contrast to ToxB, caspase inhibitors do not protect CGNs from targeted inhibition of Rac. Also dissimilar to ToxB, selective inhibition of Rac neither inhibits MEK1/2/ERK1/2 nor activates JNK/c-Jun. Targeted inhibition of Rac instead suppresses distinct MEK5/ERK5, p90Rsk and Akt-dependent signaling cascades known to regulate the localization and expression of the Bcl-2 homology-3 domain (BH3)-only protein Bad. Adenoviral expression of a constitutively active mutant of MEK5 is sufficient to attenuate neuronal cell death induced by selective inhibition of Rac with NSC23766, but not apoptosis induced by global inhibition of Rho GTPases with ToxB. Collectively, these data demonstrate that global suppression of Rho family GTPases with ToxB causes a loss of MEK1/2/ERK1/2 signaling and activation of JNK/c-Jun, resulting in diminished degradation and enhanced transcription of the BH3-only protein Bim. In contrast, selective inhibition of Rac induces CGN apoptosis by repressing unique MEK5/ERK5, p90Rsk, and Akt-dependent pro-survival pathways, ultimately leading to enhanced expression, dephosphorylation, and mitochondrial localization of pro-apoptotic Bad.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Neuronal apoptosis induced by selective inhibition of Rac GTPase versus global suppression of Rho family GTPases is mediated by alterations in distinct mitogen-activated protein kinase signaling cascades [Signal Transduction]