TI - Role of group A p21-activated kinases in activation of extracellular-regulated kinase by growth factors . AB - The canonical extracellular-regulated kinase ( ERK ) signaling cascade , consisting of the Ras-Raf-Mek-ERK module , is critically important to many cellular functions . Although the general mechanism of activation of the ERK cascade is well established , additional noncanonical components greatly influence the activity of this pathway . Here , we focus on the group A p21-activated kinases ( Paks ) , which have previously been implicated in regulating both c-Raf and Mek1 activity , by phosphorylating these proteins at Ser(338) and Ser(298) , respectively . In NIH-3T3 cells , expression of an inhibitor of all three group A Paks reduced activation of ERK in response to platelet-derived growth factor ( PDGF ) but not to epidermal growth factor ( EGF ) . Similar results were obtained in HeLa cells using small interference RNA -mediated simultaneous knockdown of both Pak1 and Pak2 to reduce group A Pak function . Inhibition of Pak kinase activity dramatically decreased phosphorylation of Mek1 at Ser(298) in response to either PDGF or EGF , but this inhibition did not prevent Mek1 activation by EGF , suggesting that although Pak can phosphorylate Mek1 at Ser(298) , this event is not required for Mek1 activation by growth factors . Inhibition of Pak reduced the Ser(338) phosphorylation of c-Raf in response to both PDGF and EGF ; however , in the case of EGF , the reduction in Ser(338) phosphorylation was not accompanied by a significant decrease in c-Raf activity . These findings suggest that Paks are required for the phosphorylation of c-Raf at Ser(338) in response to either growth factor , but that the mechanisms by which EGF and PDGF activate c-Raf are fundamentally different .