Actin cytoskeleton organization regulated by the PAK family of protein kinases

Abstract

Cdc42, Rac1 and other Rho-type GTPases regulate gene expression, cell proliferation and cytoskeletal architecture [1,2]. A challenge is to identify the effectors of Cdc42 and Rac1 that mediate these biological responses. Protein kinases of the p21-activated kinase (PAK) family bind activated Rac1 and Cdc42, and switch on mitogen-activated protein (MAP) kinase pathways; however, their roles in regulating actin cytoskeleton organization have not been clearly established [3-5]. Here, we show that mutants of the budding yeast Saccharomyces cerevisiae lacking the PAK homologs Ste20 and Cla4 exhibit actin cytoskeletal defects, in vivo and in vitro, that resemble those of cdc42-1 mutants. Moreover, STE20 overexpression suppresses cdc42-1 growth defects and cytoskeletal defects in vivo, and Ste20 kinase corrects the actin-assembly defects of permeabilized cdc42-1 cells in vitro. Thus, PAKs are effectors of Cdc42 in pathways that regulate the organization of the cortical actin cytoskeleton.

The genetics of Pak

“…The cell-cycle effects are independent of the MAPK pathway, which indicates that Ste20 has one or more additional substrates that are required for cell polarization (Eby et al, 1998;Holly and Blumer, 1999). During bud emergence, Ste20 is phosphorylated by the CDK-cyclin complex Cdc28-Cln2, and this appears to promote the vegetative morphogenetic functions of Ste20 (Oehlen and Cross, 1998;Wu et al, 1998).…”

Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1

“…The molecular signaling connection between rac1 and the actin cytoskeleton is an area of intense ongoing research with recent interest focusing on the participation of PAK. Effects of rac1 on cytoskeletal organization are mediated, in part, by activation of PAK (42,43), which phosphorylates serine/threonine residues. Activation of PAK, like rac1, leads to disassembly of focal adhesion complexes (31).…”

Comparative studies of a new subfamily of human Ste20-like kinases: homodimerization, subcellular localization, and selective activation of MKK3 and p38

“…Binding of the small guanine triphosphatases to specific consensus sequences (Manser et al, 1994), known as the CRIB (Cdc42/Rac1 interactive binding) domain, within the aminoterminus of the PAK proteins causes a conformational change and direct activation of the catalytic domain. In general, PAK kinases are implicated in the activation of the stress-activated protein kinase/jun Nterminal kinase (SAPK/JNK) pathway, as well as regulating cell morphology and cell motility through interaction and regulation of the cytoskeleton (Brown et al, 1996;Frost et al, 1996;Eby et al, 1998;Chung and Firtel, 1999;Holly and Blumer, 1999).…”