Suppression of tubulin polymerization by the LKB1-microtubule-associated protein/microtubule affinity-regulating kinase signaling
Suppression of tubulin polymerization by the LKB1-microtubule-associated protein/microtubule affinity-regulating kinase signaling
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DOI：
10.1074/jbc.m700590200
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发表时间：
2007-08-10
影响因子：
4.8
通讯作者：
Taketo, Makoto M.
中科院分区：
文献类型：
--
作者：
Kojima, Yasushi;Miyoshi, Hiroyuki;Taketo, Makoto M.
LKB1 是黑斑息肉综合征中突变的肿瘤抑制基因，编码丝氨酸/苏氨酸蛋白激酶。最近的生化研究表明，LKB1 可激活 14 种 AMP 激活的蛋白激酶相关激酶，包括调节微管动力学的 MARK（微管相关蛋白/微管亲和力调节激酶）。在这里，我们在体外证明 LKB1 磷酸化并激活 MARK2，MARK2 反过来磷酸化 KXGS 基序处的微管相关蛋白 Tau 并抑制微管蛋白聚合。在细胞中，LKB1 的强制表达会抑制微管的再生，而 LKB1 敲除则会加速微管的再生。我们进一步表明，LKB1-MARK 信号传导对 Tau 的磷酸化会触发蛋白酶体介导的 Tau 降解。这些结果表明 LKB1 通过 MARK 的激活参与微管动力学的调节。
LKB1, a tumor suppressor gene mutated in the Peutz-Jeghers syndrome, encodes a serine/threonine protein kinase. Recent biochemical studies have shown that LKB1 activates 14 AMP-activated protein kinase-related kinases including MARKs (microtubule-associated protein/microtubule affinity-regulating kinases) that regulate microtubule dynamics. Here we show in vitro that LKB1 phosphorylates and activates MARK2, which in turn phosphorylates microtubule-associated protein Tau at the KXGS motif and suppresses tubulin polymerization. In cells, forced expression of LKB1 suppresses microtubule regrowth, whereas LKB1 knockdown accelerates it. We further show that the phosphorylation of Tau by the LKB1-MARK signaling triggers proteasome-mediated degradation of Tau. These results indicate that LKB1 is involved in the regulation of microtubule dynamics through the activation of MARKs.