Group I and II mammalian PAKs have different modes of activation by Cdc42

Abstract

p21-activated kinases (PAKs) are Cdc42 effectors found in metazoans, fungi and protozoa. They are subdivided into PAK1-like (group I) or PAK4-like (group II) kinases. Human PAK4 is widely expressed and its regulatory mechanism is unknown. We show that PAK4 is strongly inhibited by a newly identified autoinhibitory domain (AID) formed by amino acids 20 to 68, which is evolutionarily related to that of other PAKs. In contrast to group I kinases, PAK4 is constitutively phosphorylated on Ser 474 in the activation loop, but held in an inactive state until Cdc42 binding. Thus, group II PAKs are regulated through conformational changes in the AID rather than A-loop phosphorylation.

P21 activated kinases

“…15,23,24 Nevertheless, group B Paks are activated by completely different mechanisms than the group A Paks, and they function as monomers rather than as dimers. 15 In fact, the group B Paks are usually found to be constitutively autophosphorylated at the A-loop, even in quiescent cells. 15 Instead of regulating A-loop autophosphorylation, the group B Pak AID is thought to allosterically modify the constitutively phosphorylated kinase so that it becomes active.…”

“…15 In fact, the group B Paks are usually found to be constitutively autophosphorylated at the A-loop, even in quiescent cells. 15 Instead of regulating A-loop autophosphorylation, the group B Pak AID is thought to allosterically modify the constitutively phosphorylated kinase so that it becomes active. 15 Exactly how the AID like domains work in the group B Paks is controversial, but one prevailing model is that the AID binds to the Pak catalytic domain in cis, which keeps the kinase in an inactive conformation, even though it is constitutively phosphorylated.…”

“…The group A and group B Paks are regulated by different mechanisms, 15,16 and the current models for the regulation of the 2 groups of Paks are shown in Figure 2. The group A Paks are notable for having an autoinhibitory domain (AID), which overlaps the GBD, and plays an important role in the control of Pak activation.…”

“…15 Instead of regulating A-loop autophosphorylation, the group B Pak AID is thought to allosterically modify the constitutively phosphorylated kinase so that it becomes active. 15 Exactly how the AID like domains work in the group B Paks is controversial, but one prevailing model is that the AID binds to the Pak catalytic domain in cis, which keeps the kinase in an inactive conformation, even though it is constitutively phosphorylated. When GTP bound Cdc42 binds the GBD, this interaction is disrupted, leading to a conformational change which results in Pak activation 15 (see Fig.…”

PAK6 targets to cell-cell adhesions via its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape

“…By contrast, type II PAKs are constitutively autophosphorylated on the activation loop and are generally not believed to be activated by GTPase binding (Ha et al, 2012(Ha et al, , 2015. Cdc42 binding has instead been proposed to determine cellular localization of type II PAKs Callow et al, 2002), although Cdc42 might also play a role in conformational activation of PAK4 (Baskaran et al, 2012).…”