The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells
The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells
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DOI：
10.1158/0008-5472.can-05-2368
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Jones, Frank E.
中科院分区：
文献类型：
--
作者：
Naresh, Anjali;Long, Weiwen;Jones, Frank E.
ERBB 4/HER 4（此处称为ERBB 4）是受体酪氨酸激酶表皮生长因子受体（EGFR）家族的独特成员。与EGFR家族的其他三个成员（即，EGFR、ERBB 2/HER 2/NEU和ERBB 3），其与人类癌症的侵袭性形式相关，EBBB 4表达似乎在具有侵袭性表型的肿瘤中选择性地丧失。与这一观察结果一致，我们表明，ERBB 4诱导细胞凋亡时，重新引入乳腺癌细胞系或内源性ERBB 4被激活的配体。我们进一步表明，内源性ERBB 4的配体激活和随后的蛋白水解加工导致ERBB 4胞内结构域（4 ICD）和细胞色素c流出的线粒体积累，这是线粒体调节细胞凋亡的必要和关键步骤。我们的研究结果表明，4 ICD是功能上类似的BH 3唯一的蛋白质，BCL-2家族的促凋亡成员需要启动线粒体功能障碍，通过激活促凋亡的多BH结构域蛋白Bax/巴克类似于其他BH 3唯一的蛋白质，4 ICD细胞杀伤活性需要一个完整的BH 3结构域和4 ICD与抗凋亡蛋白BCL-2的相互作用，抑制4 ICD诱导的细胞凋亡。然而，在仅BH 3的蛋白质中，独特的是巴克而不是BAX传递41 CD凋亡信号的基本要求。临床上，原发性人乳腺肿瘤中胞质而非膜ERBB 4/4 ICD表达与肿瘤细胞凋亡相关，为肿瘤进展期间ERBB 4表达丧失提供了机制解释。因此，我们提出，配体诱导的线粒体积累的4 ICD代表了一个独特的跨膜受体的作用机制，直接耦合到肿瘤细胞线粒体凋亡途径的细胞表面信号。
ERBB4/HER4 (referred to here as ERBB4) is a unique member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. In contrast to the other three members of the EGFR family (i.e., EGFR, ERBB2/HER2/NEU, and ERBB3), which are associated with aggressive forms of human cancers, EBBB4 expression seems to be selectively lost in tumors with aggressive phenotypes. Consistent with this observation, we show that ERBB4 induces apoptosis when reintroduced into breast cancer cell lines or when endogenous ERBB4 is activated by a ligand. We further show that ligand activation and subsequent proteolytic processing of endogenous ERBB4 results in mitochondrial accumulation of the ERBB4 intracellular domain (4ICD) and cytochrome c efflux, the essential and committed step of mitochondrial regulated apoptosis. Our results indicate that 4ICD is functionally similar to BH3-only proteins, proapoptotic members of the BCL-2 family required for initiation of mitochondrial dysfunction through activation of the proapoptotic multi-BH domain proteins BAX/BAK Similar to other BH3-only proteins, 4ICD cell-killing activity requires an intact BH3 domain and 4ICD interaction with the antiapoptotic protein BCL-2, suppressed 4ICD-induced apoptosis. Unique among BH3-only proteins, however, is the essential requirement of BAK but not BAX to transmit the 41CD apoptotic signal. Clinically, cytosolic but not membrane ERBB4/4ICD expression in primary human breast tumors was associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression. Thus, we propose that ligand-induced mitochondrial accumulation of 4ICD represents a unique mechanism of action for transmembrane receptors, directly coupling a cell surface signal to the tumor cell mitochondrial apoptotic pathway.