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Activation of PAK2 by Serum Starvation Sensitizes its Response to Insulin Treatment in Adipocyte 3T3-L1 Cells

Jun Ling, Siska Corneillie, Colby Cottell and Jolinda A Traugh

p21-activated kinase-2 (PAK2) is ubiquitously expressed in all mammalian cells and tissues tested so far. It is a unique member of PAK family kinases that can be activated by various stress conditions to induce apoptosis or cytostasis. Although many conditions have been reported to activate PAK2, serum starvation followed by insulin treatment has not been studied. In this study, pre-adipocyte (3T3-L1) sensitive to insulin signaling and important for energy homeostasis was used as the system to address this topic. It was found that serum starvation transiently activated PAK2 activity by about 3-fold within one hour, then returning to the basal level within three hours. Following the activation of PAK2 by serum starvation, insulin treatment resulted in a rapid deactivation of PAK2 through ubiquitination-proteasome mediated protein degradation. AKT1 and PAK2 activities were reversely related, suggesting that AKT1 activation could be a factor to initiate PAK2 degradation. This dynamic change of PAK2 by serum starvation and insulin was found to be correlated with the fluctuation of protein synthesis, a major biological process to influence cell growth rate. Activation of PAK2 by serum starvation was correlated with about 50% inhibition of protein synthesis; subsequent treatment with insulin reversed this inhibition. Down-regulation of PAK2 by siRNA further proved that PAK2 was a causal factor leading to the inhibition of protein synthesis. In conclusion, this study identifies a new pattern of regulation of PAK2 by serum starvation and insulin, suggests an important role of PAK2 in regulating adipocyte function in response to nutrient status and insulin signaling.