Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene.
Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene.
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DOI：
10.1016/j.ccr.2009.09.026
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发表时间：
2009-11-06
期刊：
影响因子：
50.3
通讯作者：
Bardeesy N
中科院分区：
文献类型：
--
作者：
Zhou D;Conrad C;Xia F;Park JS;Payer B;Yin Y;Lauwers GY;Thasler W;Lee JT;Avruch J;Bardeesy N
Hippo-Lats-Yorkie信号调节果蝇的组织过度生长和肿瘤发生。我们发现，Mst 1和Mst 2蛋白激酶，哺乳动物河马的直系同源物，被切割和组成性激活的小鼠肝脏。肝脏中Mst 1/2缺陷导致Yorkie直系同源物Yap 1的抑制性Ser 127磷酸化丧失，大量过度生长和肝细胞癌（HCC）。Mst 1在肝癌衍生细胞系中的再表达促进Yap 1 Ser 127磷酸化和失活，并消除其致瘤性。值得注意的是，Mst 1/2通过与Lats 1/2不同的中间激酶使肝脏中的Yap 1失活。大约30%的人HCC显示出低Yap 1（Ser 127）磷酸化，大多数显示出切割的、活化的Mst 1的丢失。Mst 1/2抑制Yap 1是肝癌相关肝脏肿瘤抑制的重要途径。调节肝脏静止和肿瘤抑制的途径尚未完全阐明。我们发现，Mst 1和Mst 2激酶是肿瘤抑制因子和成人肝脏大小的调节因子，转录辅激活因子Yap 1的负调控是Mst 1/2肿瘤抑制功能的核心。Mst 1和Mst 2的缺失足以启动肝细胞增殖，导致显著的肝脏过度生长，对促凋亡刺激的抵抗和HCC的发展。Mst 1和Mst 2促进Yap 1的磷酸化，从而抑制其致癌活性。Mst 1/2对Yap 1的调节是组织特异性的，在肝脏中，涉及与Lats 1/2不同的Mst 1/2调节的Yap 1激酶。值得注意的是，Mst-Yap 1通路在相当一部分人HCC中被破坏。
Hippo-Lats-Yorkie signaling regulates tissue overgrowth and tumorigenesis in Drosophila. We show that the Mst1 and Mst2 protein kinases, the mammalian Hippo orthologs, are cleaved and constitutively activated in the mouse liver. Combined Mst1/2 deficiency in the liver results in loss of inhibitory Ser127 phosphorylation of the Yorkie ortholog, Yap1, massive overgrowth, and hepatocellular carcinoma (HCC). Reexpression of Mst1 in HCC-derived cell lines promotes Yap1 Ser127 phosphorylation and inactivation, and abrogates their tumorigenicity. Notably, Mst1/2 inactivates Yap1 in liver through an intermediary kinase distinct from Lats1/2. Approximately 30% of human HCCs show low Yap1(Ser127) phosphorylation and a majority exhibit loss of cleaved, activated Mst1. Mst1/2 inhibition of Yap1 is an important pathway for tumor suppression in liver relevant to human HCC. The pathways that regulate quiescence and tumor suppression in the liver have not been fully elucidated. We show that the Mst1 and Mst2 kinases are tumor suppressors and regulators of liver size in adults and that negative regulation of the transcriptional coactivator, Yap1, is central to Mst1/2 tumor suppressor function. Loss of both Mst1 and Mst2 is sufficient to initiate hepatocyte proliferation, resulting in dramatic liver overgrowth, resistance to pro-apoptotic stimuli, and the development of HCC. Mst1 and Mst2 promote phosphorylation of Yap1 and thereby suppress its oncogenic activity. Mst1/2 regulation of Yap1 is tissue-specific and, in the liver, involves an Mst1/2-regulated Yap1 kinase distinct from Lats1/2. Significantly, the Mst-Yap1 pathway is disrupted in a substantial fraction of human HCCs.
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