The p21 activated protein kinases (PAK) are a growing family of serine/threonine protein kinases which are activated in response to extracellular signals and regulate diverse cellular functions including cytoskeletal actin assembly, neurite outgrowth, cell cycle control and apoptosis.The GTPase family proteins Cdc42 and Rac are the major activators of PAKs. The GTP bound forms of Cdc42 and Rac regulate assembly of the actin cytoskeleton, in part by stimulation of PAKs and in part by activation of the intermediate switch proteins, WASP and N-WASP. PAKs respond to receptor mediated signals that direct their recruitment to the plasma membrane followed by their activation. Major receptors that activate PAK signaling include RTK and integrins. Growth factors such as EGF bind and activate RTK such as EGFR which eventually results in activation of Ras. Ras then activates several effectors such as the ser/thr kinase Raf and PI3K. The PI3K pathway activates Cdc42 and Rac through Vav. Activated Cdc42 and Rac then activate PAKs. EGFR can also be linked to PAK through an adapter protein called NCK which binds PAK to form a tertiary complex of ErbB1-NCK-PAK. Furthermore, PAKs activate Raf by phosphorylating ser338, leading to the activation of ERK/MAPK signaling. Stimulation of EGFR also enhances the level of EGFR-associated PAK1 and GRB2 although the PAK1-GRB2 association is itself independent of this stimulation. ECM components interact with integrins, which via FAK and ETK activate PAK1 which eventually activates the Raf/MEK/ERK kinase cascade. DSCAM, a type I transmembrane protein directly interacts with PAK1 and also stimulates JNK and p38 MAP kinases. Interaction of hPIP1 with PAK1 inhibits the Cdc42/Rac-stimulated kinase activity through the N-terminal regulatory domain of PAK1. PAK2 on the other hand is activated in response to apoptotic stimuli such as ceramide or TNF, and by caspase cleavage followed by autophosphorylation.
Once activated, PAKs can influence actin organization and cell polarity through phosphorylation of substrates such as myosin and MLCK. PAKs also activate MAPK cascades in vertebrates and yeast, as well as the JNK and NF-κB pathways. Activation of JNK causes phosphorylation and activation of several transcription factors. Recently, a family of PIXs were identified as binding tightly to the fourth proline-rich domain in the N-terminus of PAK. PIX can regulate PAK activity both by catalyzing GTP exchange on Cdc42/Rac and by direct binding to PAK. Paxillin, a focal adhesion adaptor protein, acts as a mediator of p21 GTPase-regulated actin cytoskeletal reorganization through the recruitment to nascent focal adhesion structures of an active PAK/PIX complex, potentially via interactions with p95PKL. In contrast to the activation of PAK2 by Rac and Cdc42, cleavage and activation of PAK2 by caspases or caspase-like proteases is involved in the execution of programmed cell death. Proteolytic cleavage generates constitutively active PAK2p34, a 34 kDa C-terminal fragment. Therefore, PAK2 appears to be unique among the PAK isoforms because it can stimulate cell survival or induce cell death depending on the mechanism of activation. Stimulation of cell growth and cell survival by activated PAK appears to be involved in the development of human cancer.