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.

βPIX and GIT control cellular senescence through integrin signaling.

Cell migration requires the coordinated spatiotemporal regulation of actomyosin contraction and cell protrusion/adhesion. Nonmuscle myosin II (MII) controls Rac1 and Cdc42 activation, and cell protrusion and focal complex formation in migrating cells. However, these mechanisms are poorly understood. Here, we show that MII interacts specifically with multiple Dbl family guanine nucleotide exchange factors (GEFs). Binding is mediated by the conserved tandem Dbl homology–pleckstrin homology module, the catalytic site of these GEFs, with dissociation constants of ∼0.3 µM. Binding to the GEFs required assembly of the MII into filaments and actin-stimulated ATPase activity. Binding of MII suppressed GEF activity. Accordingly, inhibition of MII ATPase activity caused release of GEFs and activation of Rho GTPases. Depletion of βPIX GEF in migrating NIH3T3 fibroblasts suppressed lamellipodial protrusions and focal complex formation induced by MII inhibition. The results elucidate a functional link between MII and Rac1/Cdc42 GTPases, which may regulate protrusion/adhesion dynamics in migrating cells.

Cases of laboratory-confirmed SARS-CoV-2 reinfection have been reported in a number of countries. Further, the level of natural immunity induced by SARS-CoV-2 infection is not fully clear, nor is it clear if a primary infection is protective against reinfection. To investigate the potential association between serum antibody titres and reinfection of SARS-CoV-2, ferrets with different levels of NAb titres after primary SARS-CoV-2 infection were subjected to reinfection with a heterologous SARS-CoV-2 strain. All heterologous SARS-CoV-2 reinfected ferrets showed active virus replication in the upper respiratory and gastro-intestinal tracts. However, the high NAb titre group showed attenuated viral replication and rapid viral clearance. In addition, direct-contact transmission was observed only from reinfected ferrets with low NAb titres (<20), and not from other groups. Further, lung histopathology demonstrated the presence of limited inflammatory regions in the high NAb titre groups compared with control and low NAb groups. This study demonstrates a close correlation between a low NAb titre and SARS-CoV-2 reinfection in a recovered ferret reinfection model.