Silencing of ErbB3/ErbB2 Signaling by Immunoglobulin-like Necl-2
Silencing of ErbB3/ErbB2 Signaling by Immunoglobulin-like Necl-2
复制标题
DOI：
10.1074/jbc.m109.025155
复制
发表时间：
2009-08-28
影响因子：
4.8
通讯作者：
Takai, Yoshimi
中科院分区：
文献类型：
--
作者：
Kawano, Satoshi;Ikeda, Wataru;Takai, Yoshimi
ErbB 2和ErbB 3是EGF受体/ErbB家族的成员，在与配体结合时形成异二聚体，分别诱导Rac小G蛋白和Akt蛋白激酶的活化以用于细胞运动和存活。增强的ErbB 3/ErbB 2信号传导导致肿瘤发生、侵袭和转移。我们发现ErbB 3/ErbB 2信号传导受免疫球蛋白样Necl-2调节，Necl-2在各种癌细胞中下调，并作为肿瘤抑制因子。ErbB 3的胞外区，而不是ErbB 2，与Necl-2的胞外区顺式相互作用。这种相互作用降低了配体诱导的ErbB 2催化的ErbB 3酪氨酸磷酸化，并抑制了随后ErbB 3介导的Rac和Akt活化，从而抑制了癌细胞的运动和存活。Necl-2的这些抑制作用由蛋白酪氨酸磷酸酶PTPN 13介导，PTPN 13与Necl-2的胞质尾相互作用。我们在这里描述了Necl-2沉默ErbB 3/ErbB 2信号传导的新机制。
ErbB2 and ErbB3, members of the EGF receptor/ErbB family, form a heterodimer upon binding of a ligand, inducing the activation of Rac small G protein and Akt protein kinase for cell movement and survival, respectively. The enhanced ErbB3/ErbB2 signaling causes tumorigenesis, invasion, and metastasis. We found here that the ErbB3/ErbB2 signaling is regulated by immunoglobulin-like Necl-2, which is down-regulated in various cancer cells and serves as a tumor suppressor. The extracellular region of ErbB3, but not ErbB2, interacted in cis with that of Necl-2. This interaction reduced the ligand-induced, ErbB2-catalyzed tyrosine phosphorylation of ErbB3 and inhibited the consequent ErbB3-mediated activation of Rac and Akt, resulting in the inhibition of cancer cell movement and survival. These inhibitory effects of Necl-2 were mediated by the protein-tyrosine phosphatase PTPN13 which interacted with the cytoplasmic tail of Necl-2. We describe here this novel mechanism for silencing of the ErbB3/ErbB2 signaling by Necl-2.