p21-activated protein kinase gamma-PAK suppresses programmed cell death ofBALB3T3 fibroblasts

In response to stress stimulants, cells activate opposing signaling pathway s for cell survival and programmed cell death. p21-activated protein kinase gamma -PAK is involved in both cell survival and cell death pathways. Many stress stimulants activate gamma -PAK as a full-length enzyme and as a pro teolytic fragment. Caspase-mediated proteolytic activation parallels cell d eath and appears to be a pro-apoptotic factor in stress-induced cell death. Here, we show that activation of full-length gamma -PAK promotes cell surv ival and suppresses stress-induced cell death. Expression of constitutively active gamma -PAK-T402E, which mimics activated full-length gamma -PAK, st imulates cell survival of BALB3T3 fibroblasts in response to tumor necrosis factor alpha, growth factor withdrawal, and WC light. This stimulation of cell survival is mainly due to protection of cells from cell death rather t han by stimulation of proliferation. Expression of gamma -PAK-T402E increas es phosphorylation of the proapoptotic Bcl-2 family protein Bad and protect s from cell death induced by ectopic expression of Bad. In response to tumo r necrosis factor alpha, expression of gamma -PAK-T402E increases the early but reduces the late activation of ERK, JNK, and p38, Our results indicate that the ubiquitous gamma -PAK may have a crucial function in cell surviva l by regulating the pro-apoptotic activity of Bad and the stress-induced ac tivation of ERK, JNK, and p38 pathways.