Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis
Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis
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DOI：
10.1128/mcb.23.18.6350-6362.2003
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发表时间：
2003-09-01
影响因子：
5.3
通讯作者：
Yang, E
中科院分区：
文献类型：
--
作者：
Chiang, CW;Kanies, C;Yang, E
BAD是BCL2家族的促凋亡分子，受可逆磷酸化调控。在生存期间，BAD通过丝氨酸136磷酸化被14-3-3隔离，并通过丝氨酸155磷酸化与BCL-X-L分离。我们报道了磷酸丝氨酸112 （pSer112）去磷酸化在bad介导的细胞凋亡中起守门人的作用。在细胞凋亡过程中，pSer112的去磷酸化先于pSer136的去磷酸化。pSer112的去磷酸化加速了pSer136的去磷酸化，抑制pSer112的去磷酸化阻止了pSer136的去磷酸化，这表明pSer136的去磷酸化需要pSer112的去磷酸化。蛋白磷酸酶2A （PP2A）是主要的pSer112磷酸酶。PP2A与14-3-3竞争BAD结合，退出生存因子增强了PP2A与BAD的关联。关键残基pSer136的去磷酸化只能通过抑制所有已知的丝氨酸/苏氨酸磷酸酶亚家族来阻断，这表明多种磷酸酶参与了pSer136的去磷酸化。抑制PP2A使FL5.12细胞免于凋亡，证明了PP2A介导的pSer112去磷酸化的生理作用。因此，在白介素-3戒断诱导的细胞凋亡过程中，PP2A pSer112的去磷酸化是调节BAD活化的关键启动事件。
BAD, a proapoptotic molecule of the BCL2 family, is regulated by reversible phosphorylation. During survival, BAD is sequestered by 14-3-3 through serine 136 phosphorylation and is dissociated from BCL-X-L through serine 155 phosphorylation. We report that phosphoserine 112 (pSer112) dephosphorylation functions as a gatekeeper for BAD-mediated apoptosis. During apoptosis, dephosphorylation of pSer112 preceded pSer136 dephosphorylation. Dephosphorylation of pSer112 accelerated dephosphorylation of pSer136, and inhibition of pSer112 dephosphorylation prevented pSer136 dephosphorylation, indicating that dephosphorylation of pSer112 is required for dephosphorylation of pSer136. Protein phosphatase 2A (PP2A) is the major pSer112 phosphatase. PP2A competed with 14-3-3 for BAD binding, and survival factor withdrawal enhanced PP2A association with BAD. Dephosphorylation of the critical residue, pSer136, could only be blocked by inhibition of all known subfamilies of serine/threonine phosphatases, suggesting that multiple phosphatases are involved in pSer136 dephosphorylation. Inhibition of PP2A rescued FL5.12 cells from apoptosis, demonstrating a physiologic role for PP2A-mediated pSer112 dephosphorylation. Thus, PP2A dephosphorylation of pSer112 is the key initiating event regulating the activation of BAD during interleukin-3 withdrawal-induced apoptosis.