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  • In addition to regulating the LIMK pathway PAKs PAK and


    In addition to regulating the LIMK1 pathway, PAKs (PAK1 and PAK3) have been shown to modulate the ATPase activity of myosin light chain (MLC) via phosphorylation of Ser19 in hippocampal dendritic spines [13]. MLC activity guarantees long-term stability of GW3965 filaments by providing the mechanical force onto the actin cytoskeleton in response to synaptic stimulation, a process required for the long-term memory consolidation [58]. Accordingly, increased expression of PAK1 results in increased post-synaptic densities, spine number and dendritic protrusions [13]. Group II PAKs have also been suggested to control neurite outgrowth and development. Double Pak5/Pak6 knockout primary neurons display shorter neurites, which may underlie the cognitive defects observed in these mice [40]. We recently showed that a constitutively active form of PAK6 (S531N) promotes neurite outgrowth in vivo in the mouse striatum and the effect is mediated by the kinase Leucine-rich repeat kinase 2 (LRRK2) [8]. Mechanistically, upon binding of PAK6 to the GTPase/Roc domain of LRRK2 via its GBD, PAK6 undergoes autophosphorylation at S560 and promotes LIMK1 phosphorylation [8]. Interestingly, PAK5 and PAK6 have been recently shown to regulate presynaptic vesicle dynamics via direct phosphorylation of pacsin1 and synaptojanin1 [59], [60]. Pacsin1 contains a SH3 domain, involved in the binding of synaptojanin1, and possibly important in the process of group II PAK local activation upon small GTPase relocalization. Both proteins have been suggested to mediate the endocytosis of post-synaptic receptors (NMDA and AMPA) but also the uncoating of presynaptic vesicles [61], [62] and PAKs phosphorylation may represent an additional layer of control in finely regulating synaptic vesicle movements beyond regulation of local actin dynamics. PAK1 and 4 also intervene in cell survival and gene transcription. PAK1 is upstream and stimulates the phosphorylation of the death agonist Bad and protects cells from apoptosis [63]. Consistently, inhibition of PAK1 reduces Bad phosphorylation and increases apoptosis [64], [65]. PAK1 and PAK4 influences gene transcription in several ways. PAK1 is directly associated with chromatin and actively participates in the process of gene expression. PAK1 also affects gene transcription by posttranslational modification of transcriptional coregulators and transcription factors (reviewed in [66]). In addition, PAK4 interacts with and phosphorylates β-catenin on Ser675, which promotes the activity of transcription factors involved in cell survival and stabilizes β-catenin through inhibition of its degradation [67], [68]. In the brain, the activation state of PAKs is controlled upstream by hormones and growth factors. Given their relevant role in synaptic activity, it is also plausible that neurotransmitter release influences PAKs activation, although the literature on this subject is limited. Nerve growth factor (NGF) promotes neurite outgrowth of PC12 cells in a Rac/PAK1 dependent manner [69]. Muscarinic receptor stimulation coupled with epidermal growth factor (EGF) activates PAK1 in cell lines [70]. EGF is a key growth factor involved in brain development and in adult neurogenesis in the subventricular zone [71] [72]. Of note, PAK1 controls cortical development by promoting neuronal migration and there are indication linking cortical development and progenitor cell proliferation [73]. However, future studies focused on investigating whether PAKs affect neuronal migration through EGF stimulation and subsequent actin remodeling may provide novel insights. Among group II PAKs, PAK6 has been linked to steroid hormone signaling (Fig. 3A). PAK6 interacts with and phosphorylates the androgen receptor (AR), a nuclear receptor stimulated by testosterone [74], [75], [76]. PAK6 is highly co-expressed with AR and gluococorticoid receptors (GR) in brain dopaminergic regions (SN and ventral tegmental area, VTA), suggesting a role for PAK6 in modulating dopaminergic neurotransmission via steroid hormones [49]. Interestingly, stimulation of neuronal AR has been suggested as a remyelination therapy in multiple sclerosis, highlighting the importance of this signaling in maintaining neuronal function [77].