Functional analysis of Peutz-Jeghers mutations reveals that the LKB1 C-terminal region exerts a crucial role in regulating both the AMPK pathway and the cell polarity
Functional analysis of Peutz-Jeghers mutations reveals that the LKB1 C-terminal region exerts a crucial role in regulating both the AMPK pathway and the cell polarity
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DOI：
10.1093/hmg/ddi139
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发表时间：
2005-05-15
影响因子：
3.5
通讯作者：
Billaud, M
中科院分区：
文献类型：
--
作者：
Forcet, C;Etienne-Manneville, S;Billaud, M
LKB1 基因的种系突变是导致易患癌症的黑斑息肉综合征 (PJS) 的原因。 LKB1 编码丝氨酸-苏氨酸激酶，作为细胞周期、代谢和细胞极性的调节剂。大多数 PJS 错义突变会消除 LKB1 酶活性，从而损害 LKB1 的所有功能。在这里，我们研究了 PJS 和散发性肿瘤中发现的反复错义突变的功能后果，这些突变映射在 LKB1 C 末端非催化区域。我们报告这些 C 端突变既不会破坏 LKB1 激酶活性，也不会干扰 LKB1 诱导的生长停滞。然而，这些自然发生的突变减少了 LKB1 介导的 AMP 激活蛋白激酶 (AMPK) 的激活，并损害了下游信号传导。此外，C 端突变损害了 LKB1 建立和维持肠上皮细胞和迁移星形胶质细胞极性的能力。与这些发现一致的是，突变分析表明 LKB1 高蛋白在控制细胞极性方面发挥着重要作用。总体而言，我们的结果将 LKB1 C 末端区域发挥着至关重要的调节作用。我们的研究结果进一步表明，LKB1 肿瘤抑制活性可能取决于 AMPK 信号传导和细胞极化的调节。
Germline mutations of the LKB1 gene are responsible for the cancer-prone Peutz-Jeghers syndrome (PJS). LKB1 encodes a serine-threonine kinase that acts as a regulator of cell cycle, metabolism and cell polarity. The majority of PJS missense mutations abolish LKB1 enzymatic activity and thereby impair all functions assigned to LKB1. Here, we have investigated the functional consequences of recurrent missense mutations identified in PJS and in sporadic tumors which map in the LKB1 C-terminal non-catalytic region. We report that these C-terminal mutations neither disrupt LKB1 kinase activity nor interfere with LKB1-induced growth arrest. However, these naturally occuring mutations lessened LKB1-mediated activation of the AMP-activated protein kinase (AMPK) and impaired downstream signaling. Furthermore, C-terminal mutations compromise LKB1 ability to establish and maintain polarity of both intestinal epithelial cells and migrating astrocytes. Consistent with these findings, mutational analysis reveals that the LKB1 tall exerts an essential function in the control of cell polarity. Overall, our results ascribe a crucial regulatory role to the LKB1 C-terminal region. Our findings further indicate that LKB1 tumor suppressor activity is likely to depend on the regulation of AMPK signaling and cell polarization.