Expression of the ErbB4 receptor causes reversal regulation of PP2A in the Shc signal transduction pathway in human cancer cells
Expression of the ErbB4 receptor causes reversal regulation of PP2A in the Shc signal transduction pathway in human cancer cells
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ErbB4 受体的表达导致人类癌细胞 Shc 信号转导通路中 PP2A 的逆转调节
DOI：
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发表时间：
2006
影响因子：
4.3
通讯作者：
M. Hatakeyama
中科院分区：
文献类型：
--
作者：
N. Yumoto;Xiaomei Yu;M. Hatakeyama
ErbB 4受体的表达与非转移性类型的人类癌症的发病率相关，而其他ErbB受体家族（ErbB 1/EGFR、ErbB 2和ErbB 3）的过表达与转移性肿瘤的形成相关。然而，这种现象背后的分子机制一直不清楚。之前，我们证明冈田酸（OA），一种丝氨酸/苏氨酸磷酸酶PP 2A的抑制剂，刺激野生型中国仓鼠卵巢（CHO）细胞和表达ErbB 1受体的细胞中生长激素诱导的ERK磷酸化，但抑制表达ErbB 4受体的CHO细胞中ERK的激活。PP 2A被认为是生长激素刺激的信号转导通路的负调节剂，然而，这一观察结果表明，ErbB 4受体的表达逆转了PP 2A在ErbB 4信号转导通路中的调节。在本研究中，我们发现OA抑制了Shc在Tyr 317处的磷酸化，因此它下调了ErbB 4表达CHO细胞中ERK的磷酸化。因此，基础PP 2A有助于表达ErbB 4的CHO细胞中Shc Tyr 317的磷酸化，尽管如此，已经报道了PP 2A在EGF或IGF-I诱导的信号传导途径中负调节Shc酪氨酸磷酸化。通过检测表达不同类型ErbB受体的人癌细胞系的OA，我们发现ErbB 4受体表达伴随着PP 2A对MCF-7和SK-OV-3细胞系中Shc Tyr 317磷酸化及其下游ERK磷酸化的正调控，但在LNCaP和PC-3细胞中则没有。因此，PP 2A以细胞特异性方式调节ERK活性，并且推测PP 2A在ErbB 4受体信号传导途径中的不同调节可能导致癌症表型进展的差异。
Expression of ErbB4 receptor is correlated with the incidence of non-metastatic types of human cancers, whereas the overexpression of other ErbB receptor families (ErbB1/EGFR, ErbB2 and ErbB3) is correlated to the formation of metastatic tumors. However, the molecular mechanism underlying this phenomenon has been unclear. Earlier, we demonstrated that okadaic acid (OA), an inhibitor of a serine/threonine phosphatase PP2A, stimulated the growth hormone-induced ERK phosphorylation in the wild type Chinese hamster ovary (CHO) cells and the cells expressing ErbB1 receptor, but suppressed ERK activation in CHO cells that express ErbB4 receptor. PP2A had been understood as a negative regulator of the growth hormone-stimulated signal transduction pathways, however, this observation suggested that expression of ErbB4 receptor reversed the regulation of PP2A in the ErbB4 signalling pathway. In this study, we found that OA suppressed phosphorylation of Shc at Tyr317, therefore it down-regulated ERK phosphorylation in the ErbB4 expressing CHO cells. Accordingly, basal PP2A contributed to the phosphorylation of Shc Tyr317 in ErbB4 expressing CHO cells, nevertheless it had been reported that PP2A negatively regulates Shc tyrosine phosphorylation in the EGF- or IGF-I-induced signalling pathways. By testing OA for human cancer cell lines that express different types of ErbB receptors, we found that ErbB4 receptor expression was accompanied with positive regulation of PP2A for phosphorylation of Shc Tyr317 and its downstream ERK phosphorylation in MCF-7 and SK-OV-3 cell lines, but not in LNCaP and PC-3 cells. Thus, PP2A regulates the ERK activity in a cell-specific manner, and it is speculated that distinct regulation of PP2A in the ErbB4 receptor signalling pathway may cause a difference in progression of cancer phenotypes.
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影响因子：
11.2
作者：
Taosheng Chen;Richard W. Cho;P. Stork;M. J. Weber
通讯作者：
Taosheng Chen;Richard W. Cho;P. Stork;M. J. Weber
影响因子：
56.9
作者：
SKOLNIK, EY;BATZER, A;SCHLESSINGER, J
通讯作者：
SCHLESSINGER, J
影响因子：
56.9
作者：
SLAMON, DJ;CLARK, GM;MCGUIRE, WL
通讯作者：
MCGUIRE, WL
影响因子：
4.8
作者：
Resjö, S;Göransson, O;Degerman, E
通讯作者：
Degerman, E