Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway
Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway
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DOI：
10.1016/s0960-9822(01)00538-3
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发表时间：
2001-11-13
期刊：
影响因子：
9.2
通讯作者：
Pendergast, AM
中科院分区：
文献类型：
--
作者：
Echarri, A;Pendergast, AM
C-Abl是一种在细胞中受到严格调控的非受体酪氨酸激酶。来自果蝇和小鼠研究的遗传数据强烈支持Abl激酶在细胞骨架调节中的作用（综述见[1，2]）。C-Abl可被多种刺激激活，包括氧化应激[3]、DNA损伤[4]、整合素接合[5]、生长因子和Src家族激酶[6]。结构改变引起c-Abl酪氨酸激酶的组成性激活，导致致癌转化。虽然激活c-Abl的机制开始被阐明，很少有人知道关于下调激活c-Abl的机制，在这里，我们首次表明，激活c-Abl是下调的泛素依赖性降解途径。活化形式的c-Abl比野生型和激酶失活形式更不稳定。此外，26 S蛋白酶体的抑制导致体外和细胞中c-Abl水平增加，并且活化的c-Abl蛋白在体内被泛素化。值得注意的是，抑制成纤维细胞中的26 S蛋白酶体增加酪氨酸磷酸化的内源性c-Abl的水平。我们的数据表明，一种新的机制，不可逆的下调激活c-Abl，这是至关重要的，以防止有害的后果c-Abl过度激活的促有丝分裂和细胞骨架途径。
C-Abl is a nonreceptor tyrosine kinase that is tightly regulated in the cell. Genetic data derived from studies in flies and mice strongly support a role for Abl kinases in the regulation of the cytoskeleton (reviewed in [1, 2]). C-Abl can be activated by several stimuli, including oxidative stress [3], DNA damage [4], integrin engagement [5], growth factors, and Src family kinases [6]. Structural alterations elicit constitutive activation of the c-Abl tyrosine kinase, leading to oncogenic transformation. While the mechanisms that activate c-Abl are beginning to be elucidated, little is known regarding the mechanisms that downregulate activated c-Abl. Here, we show for the first time that activated c-Abl is downregulated by the ubiquitin-dependent degradation pathway. Activated forms of c-Abl are more unstable than wild-type and kinase-inactive forms. Moreover, inhibition of the 26S proteasome leads to increased c-Abl levels in vitro and in cells, and activated c-Abl proteins are ubiquitinated in vivo. Significantly, inhibition of the 26S proteasome in fibroblasts increases the levels of tyrosine-phosphorylated, endogenous c-Abl. Our data suggest a novel mechanism for irreversible downregulation of activated c-Abl, which is critical to prevent the deleterious consequences of c-Abl hyperactivation in mitogenic and cytoskeletal pathways.