PP2C family members play key roles in regulation of cell survival and apoptosis
PP2C family members play key roles in regulation of cell survival and apoptosis
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DOI：
10.1111/j.1349-7006.2006.00219.x
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发表时间：
2006-07
期刊：
影响因子：
5.7
通讯作者：
S. Tamura;Shinnosuke Toriumi;J. Saito;K. Awano;Tada-Aki Kudo;Takayasu Kobayashi
中科院分区：
文献类型：
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作者：
S. Tamura;Shinnosuke Toriumi;J. Saito;K. Awano;Tada-Aki Kudo;Takayasu Kobayashi
尽管癌细胞的无限增殖受到参与增殖、存活和凋亡调节的多种信号通路的支持，但是协调这些不同通路以促进癌细胞增殖和存活的分子机制仍然不清楚。SAPK和整合素-ILK信号通路分别在促进细胞凋亡和细胞增殖/存活中发挥关键作用。对TNFα和H2 O2诱导的细胞凋亡的研究表明，ASK 1是SAPK系统的一个组成部分，介导了TNFα和H2 O2信号转导。在TNFα刺激后，ASK 1通过特定苏氨酸残基（T845）的自磷酸化激活。我们最近的研究表明，PP 2C家族的一员PP 2C β通过去磷酸化T845与ASK 1结合并使其失活。相比之下，PP 2C δ/ILKAP，第二个PP 2C家族成员，通过增强T845的细胞磷酸化来激活ASK 1。PP 2C δ/ILKAP还与ILK 1形成复合物，以在体内抑制GSK 3 β介导的整合素-ILK 1信号传导，从而抑制细胞周期进程。这些观察结果提出了PP 2C δ/ILKAP用于控制整合素诱导的和TNFα诱导的信号通路之间的串扰的可能性，抑制前者并刺激后者，从而抑制癌细胞的增殖和存活并促进癌细胞的凋亡。（Cancer Sci 2006; 97：563-567）
Although unlimited proliferation of cancer cells is supported by multiple signaling pathways involved in the regulation of proliferation, survival, and apoptosis, the molecular mechanisms coordinating these different pathways to promote the proliferation and survival of cancer cells have remained unclear. SAPK and integrin‐ILK signaling pathways play key roles in the promotion of apoptosis and cell proliferation/survival, respectively. Studies of TNFα‐ and H2O2‐induced apoptosis revealed that ASK1, a component of the SAPK system, mediates the TNFα and H2O2 signaling of apoptosis. ASK1 is activated by autophosphorylation of a specific threonine residue (T845) following TNFα stimulation. Our recent studies indicate that PP2Cɛ, a member of the PP2C family, associates with and inactivates ASK1 by dephosphorylating T845. In contrast, PP2Cδ/ILKAP, a second PP2C family member, activates ASK1 by enhancing cellular phosphorylation of T845. PP2Cδ/ILKAP also forms a complex with ILK1 to inhibit the GSK3β‐mediated integrin‐ILK1 signaling in vivo, inhibiting cell cycle progression. These observations raise the possibility that PP2Cδ/ILKAP acts to control the cross‐talk between integrin‐induced and TNFα‐induced signaling pathways, inhibiting the former and stimulating the latter, thereby inhibiting proliferation and survival and promoting the apoptosis of cancer cells. (Cancer Sci 2006; 97: 563–567)