p21-activated protein kinase γ-PAK suppresses programmed cell death of BALB3T3 fibroblasts
p21-activated protein kinase γ-PAK suppresses programmed cell death of BALB3T3 fibroblasts
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DOI：
10.1074/jbc.m007753200
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发表时间：
2001-05-18
影响因子：
4.8
通讯作者：
Koeppel, MA
中科院分区：
文献类型：
--
作者：
Jakobi, R;Moertl, E;Koeppel, MA
为了响应应激刺激物，细胞激活细胞存活和程序性细胞死亡的相反信号通路。p21激活的蛋白激酶γ-PAK参与细胞存活和细胞死亡途径。许多应激刺激物激活γ-PAK作为全长酶和作为蛋白水解片段。半胱天冬酶介导的蛋白水解激活与细胞死亡平行，并且似乎是应激诱导的细胞死亡中的促凋亡因子。在这里，我们表明，激活全长γ-PAK促进细胞存活和抑制应激诱导的细胞死亡。组成型活性γ-PAK-T402 E（其模拟活化的全长γ-PAK）的表达刺激响应于肿瘤坏死因子α、生长因子撤回和WC光的BALB 3 T3成纤维细胞的细胞存活。这种细胞存活的刺激主要是由于保护细胞免于细胞死亡，而不是通过刺激增殖。γ-PAK-T402 E的表达增加了促凋亡Bcl-2家族蛋白Bad的磷酸化，并保护免于由Bad的异位表达诱导的细胞死亡。响应于肿瘤坏死因子α，γ-PAK-T402 E的表达增加了ERK、JNK和p38的早期激活，但减少了晚期激活。我们的结果表明，普遍存在的γ-PAK可能通过调节Bad的促凋亡活性和应激诱导的ERK、JNK和p38通路的激活而在细胞存活中具有关键功能。
In response to stress stimulants, cells activate opposing signaling pathways 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 proteolytic fragment. Caspase-mediated proteolytic activation parallels cell death 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 survival and suppresses stress-induced cell death. Expression of constitutively active gamma -PAK-T402E, which mimics activated full-length gamma -PAK, stimulates 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 than by stimulation of proliferation. Expression of gamma -PAK-T402E increases phosphorylation of the proapoptotic Bcl-2 family protein Bad and protects from cell death induced by ectopic expression of Bad. In response to tumor 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 survival by regulating the pro-apoptotic activity of Bad and the stress-induced activation of ERK, JNK, and p38 pathways.