Fig. 4: PAK4-mediated signaling pathways in PD.
From: PAK4 signaling in health and disease: defining the PAK4–CREB axis
In the cytosol, CRTC1 is phosphorylated at S151 by the cAMP-SIK pathway and is inactivated through interactions with 14–3–3 proteins12. Ca2 + influx through L-type VGCCs stimulates calcineurin-dependent CRTC1 dephosphorylation12. CRTC1 is activated by calcineurin-dependent dephosphorylation12. Dephosphorylated CRTC1 is translocated to the nucleus, where it is likely phosphorylated at S215 by PAK4, which triggers CREB-mediated transcription. In PD, oxidative stress and aggregated α-Syn decrease PAK4 activity and reduce pCRTC1S215 levels, which subsequently decrease the expression of CREB target genes such as BDNF, Bcl-2, and PGC-1α, leading to dopaminergic neuron death. CRE, cAMP response element; CREB CRE-binding protein, CRTC1 CREB-regulated transcription coactivator 1, CBP CREB-binding protein, SIK1 salt-inducible kinase 1, VGCC voltage-gated calcium channel, BDNF brain-derived neurotrophic factor, Bcl-2 B-cell lymphoma 2, PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1 alpha, TH tyrosine hydroxylase
