The P21-Activated Kinase 1 and 2 As Potential Therapeutic Targets for the Management of Cardiovascular Disease

Figures

• 

  Figure 1. Structural domains of Pak1 and Pak2. Nck and PIX are the two SH3-binding domains (orange); the autoinhibition dimer interface (purple) overlaps with the p21-binding domain and inhibitory region (AID) (brown); the kinase domain is at the C-terminus (blue); activation dimer interface is within the kinase domain (yellow).

• 

  Figure 2. The signalling nexus of Pak1 and Pak2. Mechanisms underlying the multiple physiological effects of Paks. Pak1/2 phosphorylate myosin light chain (MLC) to regulate endothelial cell migration and contractility. Pak1 phosphorylates Bad to inhibit its interaction with Bcl2 to prevent apoptosis. Pak1 exerts anti-apoptotic effects via the p53/p21signalling pathway. Pak1 acetylation can phosphorylate ATG5 to promote autophagosome formation. Pak2 enhances Smad2/3 activation and upregulates Sec62 expression to promote autophagy. Pak1 regulates NDUFA12 expression level to modulate mitochondrial function. Pak2 regulates fatty acid oxidation and mitochondrial homeostasis by acting through the ERK5/PGC-1α pathway. Pak2 regulates Nrf2 expression and the subsequent ROS production. Pak2 maintains ER function and proteostasis via the IRE1/XBP1 signalling pathway. Pak1 activates NFκB to influence immune responses. Pak2 regulates M1 macrophage polarization to play anti-inflammatory roles. ER: Endoplasmic Reticulum; REDOX: Reduction-Oxidation.