麻省總醫(yī)院分子生物部,，糖尿病研究所,，癌癥研究中心，哈佛醫(yī)學(xué)院的科學(xué)家在最新的Cancer Cell上發(fā)表肝癌研究新進(jìn)展,，Mst1 and Mst2 Maintain Hepatocyte Quiescence and Suppress Hepatocellular Carcinoma Development through Inactivation of the Yap1 Oncogene,。
在果蠅模型中，Hippo-Lats-Yorkie信號通路參與細(xì)胞過度生長,，以及腫瘤的發(fā)生,。在哺乳動物中，類似Hippo-Lats-Yorkie的是Mst1和Mst2,。這項(xiàng)新的研究發(fā)現(xiàn),，Mst1和Mst2在肝癌的發(fā)展過程中具有抑制癌癥發(fā)生的作用。
Hippo腫瘤抑制途徑是控制果蠅組織大小的一個關(guān)鍵的信號途徑,。Hippo信號途徑通過促進(jìn)細(xì)胞凋亡和細(xì)胞周期停滯來限制組織的大小,。而且攜帶hippo突變的果蠅，其成熟結(jié)構(gòu)會發(fā)生嚴(yán)重的過度生長,。 Hippo途徑一直被認(rèn)為是通過轉(zhuǎn)錄共活化因子Yorkie的磷酸化來調(diào)節(jié)基因表達(dá),，進(jìn)而執(zhí)行這種限制組織尺寸的功能。
蛋白激酶MST(Mammalian Sterile20-like Kinase) 是各種組織都有表達(dá)的絲氨酸/蘇氨酸（Serine/Threonine）蛋白激酶,。屬于人絲氨酸/蘇氨酸激酶的哺乳動物STE20樣激酶(MST),，與芽殖酵母激酶 SPS1 和STE2在其激酶結(jié)構(gòu)域上具有相當(dāng)大的同源性。當(dāng)在 HeLa細(xì)胞中穩(wěn)定表達(dá)時,，MST 通過加速胱冬蛋白酶3的活化使細(xì)胞對死亡受體介導(dǎo)的細(xì)胞凋亡高度敏感,。這些發(fā)現(xiàn)表明，MST1和MST2在胱冬蛋白酶激活的細(xì)胞凋亡的上游和下游都起作用,。 細(xì)胞凋亡中MST1被胱冬蛋白酶切割和激活,，能誘導(dǎo)細(xì)胞凋亡形態(tài)上的改變?nèi)缛旧|(zhì)凝聚。哺乳動物STE20樣激酶2 (Mst2) 與先前鑒定的 Mst1蛋白激酶很相似 (78% 相同,，88% 相似) ,。Northern 分析表明，MST2 mRNA在成人腎,、骨骼和胎盤組織中高水平表達(dá),，在成人心、肺,、肝和腦組織中表達(dá)水平非常低,。體外激酶試驗(yàn)表明，Mst2 能對外源底物進(jìn)行磷酸化,，也能對其本身進(jìn)行磷酸化,，磷酸化氨基酸分析表明，它是一種絲氨酸/蘇氨酸蛋白激酶,。
在新的研究中,，科學(xué)家們發(fā)現(xiàn)Mst1/Mst2的缺失將導(dǎo)致Yap1 Ser127抑制劑缺失，誘發(fā)細(xì)胞過度生長導(dǎo)致肝細(xì)胞癌（HCC）的發(fā)生,。若重新表達(dá)Mst1/Mst2,，將促進(jìn)Yap1 Ser127磷酸化，抑制它們的促癌功能,。
這些研究結(jié)果表明,，Mst1/Mst2具有明顯的抑制Yap1 Ser127的功能，這是抑制人類肝細(xì)胞癌的發(fā)生的重要調(diào)控機(jī)制,。（生物谷Bioon.com）
生物谷推薦原始出處：
Cancer Cell, Volume 16, Issue 5, 425-438, 3 November 2009 doi:10.1016/j.ccr.2009.09.026
Mst1 and Mst2 Maintain Hepatocyte Quiescence and Suppress Hepatocellular Carcinoma Development through Inactivation of the Yap1 Oncogene
Dawang Zhou1, 2, Claudius Conrad3, 4, 11, Fan Xia1, 2, 11, Ji-Sun Park3, Bernhard Payer1, 6, Yi Yin1, 2, Gregory Y. Lauwers5, 8, Wolfgang Thasler10, Jeannie T. Lee1, 6, 8, 9, Joseph Avruch1, 2, 7, , and Nabeel Bardeesy3, 7, ,
1 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
2 Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA
3 Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA
4 Surgical Services, Massachusetts General Hospital, Boston, MA 02114, USA
5 Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
6 Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA
7 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
8 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
9 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
10 Department of Surgery, LM University Munich, Hospital Grosshadern, D-81377 Munich, Germany
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.
