Interaction between Her2 and Beclin-1 Proteins Underlies a New Mechanism of Reciprocal Regulation
Interaction between Her2 and Beclin-1 Proteins Underlies a New Mechanism of Reciprocal Regulation
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DOI：
10.1074/jbc.m113.461350
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发表时间：
2013-07-12
影响因子：
4.8
通讯作者：
Rabinowich, Hannah
中科院分区：
文献类型：
--
作者：
Han, Jie;Hou, Wen;Rabinowich, Hannah
Beclin-1是自噬的关键调节因子，其在自噬体的起始和成熟中的两个阶段特异性复合物的背景下起作用。其已知的相互作用蛋白包括自噬效应子、Bcl-2家族成员和细胞器膜锚蛋白。在这里，我们报告一个新发现的相互作用Beclin-1和蛋白酪氨酸激酶受体Her 2。我们证明，在表达Her 2的乳腺癌细胞不屈服于拉帕替尼，这种Her 1/2抑制剂破坏Her 2和Beclin-1之间的细胞表面相互作用。这些数据表明，随后的自噬反应与Beclin-1从其与Her 2的复合物中的释放以及随后的胞质Beclin-1的增加相关。Beclin-1与Her 2相互作用后，可上调Her 2和Akt的磷酸化水平。Beclin-1进化上保守的结构域是Beclin-1与Her 2相互作用以及增加Her 2和Akt磷酸化所必需的。这些发现为拉帕替尼介导的Her 2表达乳腺癌细胞系自噬和Beclin-1信号转导机制提供了新的线索。
Beclin-1 is a key regulator of autophagy that functions in the context of two phase-specific complexes in the initiation and maturation of autophagosomes. Its known interacting proteins include autophagy effectors, Bcl-2 family members, and organelle membrane anchor proteins. Here we report a newly identified interaction between Beclin-1 and the protein tyrosine kinase receptor Her2. We demonstrate that in Her2-expressing breast carcinoma cells that do not succumb to lapatinib, this Her1/2 inhibitor disrupts the cell surface interaction between Her2 and Beclin-1. The data suggest that the ensuing autophagic response is correlatively associated with the release of Beclin-1 from its complex with Her2 and with the subsequent increase in cytosolic Beclin-1. Upon its interaction with Her2, Beclin-1 up-regulates the phosphorylation levels of Her2 and Akt. The Beclin-1 evolutionarily conserved domain is required both for the interaction of Beclin-1 with Her2 and for the increased Her2 and Akt phosphorylation. These findings shed new light on mechanisms involved in lapatinib-mediated autophagy in Her2-expressing breast carcinoma cell lines and in Beclin-1 signaling in these cells.