PAK4 signaling in health and disease: defining the PAK4-CREB axis

Abstract

p21-Activated kinase 4 (PAK4), a member of the PAK family, regulates a wide range of cellular functions, including cell adhesion, migration, proliferation, and survival. Dysregulation of its expression and activity thus contributes to the development of diverse pathological conditions. PAK4 plays a pivotal role in cancer progression by accelerating the epithelial-mesenchymal transition, invasion, and metastasis. Therefore, PAK4 is regarded as an attractive therapeutic target in diverse types of cancers, prompting the development of PAK4-specific inhibitors as anticancer drugs; however, these drugs have not yet been successful. PAK4 is essential for embryonic brain development and has a neuroprotective function. A long list of PAK4 effectors has been reported. Recently, the transcription factor CREB has emerged as a novel effector of PAK4. This finding has broad implications for the role of PAK4 in health and disease because CREB-mediated transcriptional reprogramming involves a wide range of genes. In this article, we review the PAK4 signaling pathways involved in prostate cancer, Parkinson's disease, and melanogenesis, focusing in particular on the PAK4-CREB axis.

Fig. 1. Domain architecture of PAK family kinases.

Group I PAKs contain an overlapping PBD and AID in their N-terminal regions. Among the group II PAKs, PAK5 also contains a PBD and an AID. In contrast, PAK4 and PAK6 lack the AID but contain the PBD and PSD. Group II PAKs all contain a polybasic region (PBR), but its role has only been defined for PAK4 (see the main text for detail). N-lobe N-terminal lobe, C-lobe C-terminal lobe

Fig. 2. Domain architecture of CREB and its coactivators.

The functional domains and major phosphorylation sites of CREB and its coactivators are shown. Kinases responsible for phosphorylating each amino acid residue are also depicted. KID kinase-inducible domain, CBD CREB-binding domain, NLS nuclear localization signal, NES nuclear export signal, SD splicing domain, TAD transactivation domain, RID nuclear receptor interaction domain, CH Cys- and His-rich region, KIX KID-interacting domain, HAT histone acetyltransferase

Fig. 3. PAK4-mediated signaling pathways in cancer.

PAK4 is activated by various extracellular signals through receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), ERs, ARs, and WNT-FZD receptors. Activated PAK4 regulates cell proliferation, survival, invasion, metastasis, the epithelial-mesenchymal transition (EMT), and drug resistance in cancers (see the main text for a detailed description). In GPCR and RTK signaling, PKA and Ras, respectively, function upstream of PAK4. The upstream regulators of PAK4 in ER/AR and WNT signaling remain to be determined. HGF hepatocyte growth factor, LPS lipopolysaccharide

Fig. 4. PAK4-mediated signaling pathways in PD.

In the cytosol, CRTC1 is phosphorylated at S151 by the cAMP-SIK pathway and is inactivated through interactions with 14–3–3 proteins. Ca^{2 +} influx through L-type VGCCs stimulates calcineurin-dependent CRTC1 dephosphorylation. CRTC1 is activated by calcineurin-dependent dephosphorylation. 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 pCRTC1^S215 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

Fig. 5. PAK4-mediated signaling pathways in melanogenesis.

PAK4 is activated downstream of PKA in the α-MSH signaling pathway and activates the CREB–MITF pathway. PAK4 phosphorylates β-catenin and activates TCF/LEF-dependent transcription, but the Wnt ligands that activate PAK4 remain unclear. PAK4 also functions downstream of Ras, but the exact mechanism is unknown. MITF microphthalmia-associated transcription factor