The hepatocyte growth factor isoform NK2 activates motogenesis and survival but not proliferation due to lack of Akt activation.
The hepatocyte growth factor isoform NK2 activates motogenesis and survival but not proliferation due to lack of Akt activation.
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DOI：
10.1016/j.cellsig.2016.05.012
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发表时间：
2016-08
影响因子：
4.8
通讯作者：
Day RM
中科院分区：
文献类型：
--
作者：
Mungunsukh O;Lee YH;Bottaro DP;Day RM
肝细胞生长因子（HGF）是一种参与细胞增殖、迁移和形态发生的多效因子。 HGF 在胚胎发生过程中是正常组织和器官发育所必需的，但在成人中，HGF 已被证明可以驱动正常组织修复并抑制纤维化重塑。由于选择性剪接，HGF 具有两种天然存在的人类亚型：NK1 和 NK2。 NK1 被定义为 HGF 受体 Met 的激动剂，而 NK2 被定义为部分 Met 拮抗剂。此外，在纤维化重塑的条件下，NK2 仍然表达，而全长 HGF 受到抑制。此外，NK2 部分通过 Met 发出信号的机制尚不完全清楚。在这里，我们研究了 NK2 与全长 HGF 在原代人支气管上皮细胞 (BEpC) 和牛肺动脉内皮细胞 (PAEC) 中的促有丝分裂、运动和抗凋亡活性。在人 BEpC 中，NK2 部分激活 Met，诱导酪氨酸激酶结构域中 Y1234/1235 位点的 Met 磷酸化，但在多功能对接结构域中的 Y1349 位点不诱导 Met 磷酸化。 NK2 对 Met 的部分磷酸化导致 MAPK 和 STAT3 激活，但不激活 AKT。这与 MAPK 依赖性方式的运动发生和存活相关，但与细胞增殖无关。组成型活性 AKT 的过度表达补充了 NK2 信号传导，使 NK2 能够诱导细胞增殖。这些数据表明 NK2 和 HGF 驱动运动发生和抗凋亡信号传导，但只有 HGF 通过激活 AKT 途径信号传导来驱动细胞增殖。这些结果对促纤维化条件下两种亚型的差异调节的生物学后果具有影响。
Hepatocyte growth factor (HGF) is a pleiotrophic factor involved in cellular proliferation, migration and morphogenesis. HGF is required for normal tissue and organ development during embryogenesis, but in the adult HGF has been demonstrated to drive normal tissue repair and inhibit fibrotic remodeling. HGF has two naturally occurring human isoforms as a result of alternative splicing, NK1 and NK2. While NK1 has been defined as an agonist for HGF receptor, Met, NK2 is defined as a partial Met antagonist. Furthermore, under conditions of fibrotic remodeling, NK2 is still expressed while full length HGF is suppressed. Furthermore, the mechanism by which NK2 partially signals through Met is not completely understood. Here, we investigated the mitogenic, motogenic, and anti-apoptotic activities of NK2 compared with full length HGF in primary human bronchial epithelial cells (BEpC) and bovine pulmonary artery endothelial cells (PAEC). In human BEpC, NK2 partial activated Met, inducing Met phosphorylation at Y1234/1235 in the tyrosine-kinase domain but not at Y1349 site in the multifunctional docking domain. Partial phosphorylation of Met by NK2 resulted in activation of MAPK and STAT3, but not AKT. This correlated with motogenesis and survival in a MAPK-dependent manner, but not cell proliferation. Overexpression of a constitutively active AKT complemented NK2 signaling, allowing NK2 to induce cell proliferation. These data indicate that NK2 and HGF drive motogenic and anti-apoptotic signaling but only HGF drives cell proliferation by activating AKT-pathway signaling. These results have implications for the biological consequences of differential regulation of the two isoforms under pro-fibrotic conditions.
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影响因子：
4.4
作者：
Kakazu, A;Chandrasekher, G;Bazan, HEP
通讯作者：
Bazan, HEP
影响因子：
6.7
作者：
Hagiwara, Satoshi;Otsuka, Toshiyuki;Mori, Masatomo
通讯作者：
Mori, Masatomo
影响因子：
56.9
作者：
BOTTARO, DP;RUBIN, JS;AARONSON, SA
通讯作者：
AARONSON, SA
影响因子：
5.1
作者：
Azuma, J.;Taniyama, Y.;Morishita, R.
通讯作者：
Morishita, R.
DOI：
10.1073/pnas.97.4.1578
发表时间：
2000-02-15
影响因子：
11.1
作者：
Deng, XM;Ruvolo, P;May, WS
通讯作者：
May, WS