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Cancer Res:浙江大学赵斌研究组阐述调控Hippo通路的新机制

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摘要 : 2017年7月28日,国际著名肿瘤学杂志《Cancer Research》上在线发表了浙江大学生命科学研究院赵斌教授实验室题为论文

2017年7月28日,国际著名肿瘤学杂志《Cancer Research》上在线发表了浙江大学生命科学研究院赵斌教授实验室题为论文“Src inhibits the Hippo tumor suppressor pathway through tyrosine phosphorylation of Lats1”,博士研究生司渊是本文第一作者,赵斌教授是本文通讯作者。

Hippo信号转导通路在器官大小调控、癌症发生、组织再生、以及干细胞的功能上发挥重要作用。在动物模型中,Hippo信号通路失活引起器官的异常增大并伴随肿瘤的发生。在很多人类癌症中发现了Hippo信号通路的异常,但目前失调的机制还不是很清楚。

本研究发现了Hippo通路关键激酶Lats1受酪氨酸磷酸化调控的新机制。在细胞黏着条件下,Src被激活并在多个位点上直接磷酸化Lats1。细胞培养和小鼠皮下移植瘤研究模型表明Src抑制Lats1的抑癌作用,并且YAP对Src诱导的肿瘤发生起重要作用。通过癌症组织芯片免疫组织化学染色发现在人乳腺癌中Src的蛋白水平和去磷酸化的活化YAP的积累呈正相关关系。这些发现揭示了Src对Lats1的酪氨酸磷酸化是细胞黏着调控Hippo信号通路的新机制,并提示Src的激活对于肿瘤发生中YAP的失调可能起重要作用,为进一步阐明Hippo信号通路在癌症中失调的机制和开发靶向治疗方案提供了新的思路。

Cancer Res:浙江大学赵斌研究组阐述调控Hippo通路的新机制
原文链接:

Src inhibits the Hippo tumor suppressor pathway through tyrosine phosphorylation of Lats1.

原文摘要:

The Hippo pathway regulates cell proliferation, apoptosis and stem cell self-renewal and its inactivation in animal models causes organ enlargement followed by tumorigenesis. Hippo pathway deregulation occurs in many human cancers but the underlying mechanisms are not fully understood. Here we report tyrosine phosphorylation of the Hippo pathway tumor suppressor LATS1 as a mechanism underlying its regulation by cell adhesion. A tyrosine kinase library screen identified Src as the kinase to directly phosphorylate LATS1 on multiple residues, causing attenuated Mob kinase activator binding and structural alteration of the substrate-binding pocket in the kinase domain. Cell matrix adhesion activated the Hippo pathway effector transcription co-activator YAP partially through Src-mediated phosphorylation and inhibition of LATS1. Aberrant Src activation abolished the tumor suppressor activity of LATS1 and induced tumorigenesis in a YAP-dependent manner. Protein levels of Src in human breast cancer tissues correlated with accumulation of active YAP dephosphorylated on the LATS1 target site. These findings reveal tyrosine phosphorylation of LATS1 by Src as a novel mechanism of Hippo pathway regulation by cell adhesion and suggest Src activation as an underlying reason for YAP deregulation in tumorigenesis.

doi:10.1158/0008-5472.CAN-17-0391.

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