The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death
The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death
复制标题
DOI：
10.1074/jbc.m307933200
复制
发表时间：
2003-11-14
影响因子：
4.8
通讯作者：
Lilly, M
中科院分区：
文献类型：
--
作者：
Yan, B;Zemskova, M;Lilly, M
造血生长因子介导造血细胞的存活和增殖，但这些蛋白质产生作用的机制尚不完全清楚。最近的研究发现，Pim蛋白家族是细胞因子依赖的生存信号的中介物。一些研究已经确定了Pim-1激酶的底物，但对其他家族成员Pim-2和Pim-3知之甚少。我们研究了Pim-2激酶在因子依赖的小鼠造血细胞中的潜在功能。我们发现，与Pim-1类似，Pim-2mRNA和蛋白的表达也受细胞因子的调节。在细胞因子处理的细胞中产生三种PIM-2蛋白亚型。这三种形式都是活性激酶，其中短形式(PIM-2(34 KDa))在细胞因子停用后提高FDCP1细胞的存活率方面最为活跃。这种促进生存的功能包括抑制细胞凋亡和激活caspase。PIM-2(34 KDa)蛋白的强制表达似乎不能调节bcl2、bclxl、bim或bax蛋白的表达。然而，该激酶可以磷酸化丝氨酸112上的促凋亡蛋白BAD，这在一定程度上解释了它逆转Bad诱导的细胞死亡的能力。我们的结果表明，Pim-2的功能类似于Pim-1，是一种促进生存的激酶，提示BAD是一种合法的PIM-2底物。
Hematopoietic growth factors mediate the survival and proliferation of blood-forming cells, but the mechanisms through which these proteins produce their effects are incompletely known. Recent studies have identified the pim family of kinases as mediators of cytokine-dependent survival signals. Several studies have identified substrates for the pim-1 kinase, but little is known about the other family members, pim-2 and pim-3. We have investigated potential functions for the pim-2 kinase in factor-dependent murine hematopoietic cells. We find that pim-2 mRNA and protein expression are regulated by cytokines similarly to pim-1. Three PIM-2 protein isoforms are produced in cytokine-treated cells. All three forms are active kinases, and the short (PIM-2(34 kDa)) form is the most active at enhancing survival of FDCP1 cells after cytokine withdrawal. This pro-survival function involves inhibition of apoptosis and caspase activation. Enforced expression of PIM-2 (34 kDa) kinase does not appear to regulate expression of BCL-2, BCL-xL, BIM, or BAX proteins. However, the kinase can phosphorylate the pro-apoptotic protein BAD on serine 112, which accounts in part for its ability to reverse Bad-induced cell death. Our results indicate that pim-2 functions similarly to pim-1 as a pro-survival kinase and suggest that BAD is a legitimate PIM-2 substrate.