TGF-β and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions
TGF-β and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions
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DOI：
10.1038/sj.onc.1207981
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发表时间：
2004-09-23
期刊：
影响因子：
8
通讯作者：
Okazaki, K
中科院分区：
文献类型：
--
作者：
Mori, S;Matsuzaki, K;Okazaki, K
虽然肝细胞生长因子（HGF）可以与转化生长因子-β（TGF-β）信号转导协同或拮抗地起作用，但它们相互作用的分子机制仍然未知。使用抗体，选择性区分受体调节Smads（R-Smads）磷酸化的连接区从那些在C-末端区域，我们在此表明，无论是HGF或TGF-β处理正常胃源性细胞激活JNK途径，然后诱导内源性R-Smads磷酸化的连接区。然而，在它们的C-末端区域的磷酸化不被HGF处理诱导。活化的JNK可以在体外直接磷酸化R-Smads，其位点与体内对TGF-β或HGF的反应中磷酸化的位点相同。因此，R-Smads的接头区域是HGF和TGF-β信号传导途径的共同磷酸化位点。通过同时用HGF和TGF-β处理诱导的磷酸化允许R-Smads与Smad 4缔合并易位到细胞核中。JNK通路涉及HGF和TGF-β介导的浸润效力，因为JNK抑制剂SP 600125引起由HGF和TGF-β信号诱导的侵袭能力降低。此外，HGF和TGF-β的联合治疗通过Smad 3在接头区域的磷酸化导致纤溶酶原激活物抑制剂1型转录活性的有效增加。相比之下，HGF处理减少了TGF-β依赖的p15（INK 4 B）启动子的激活，其中涉及C-末端区域的Smad 3磷酸化。总之，HGF和TGF-β通过JNK介导的R-Smads磷酸化在接头区域传递信号。
Although hepatocyte growth factor (HGF) can act synergistically or antagonistically with transforming growth factor-beta (TGF-beta) signaling, molecular mechanism of their crosstalk remains unknown. Using antibodies which selectively distinguished receptor-regulated Smads (R-Smads) phosphorylated at linker regions from those at C-terminal regions, we herein showed that either HGF or TGF-beta treatment of normal stomach-origin cells activated the JNK pathway, thereafter inducing endogenous R-Smads phosphorylation at linker regions. However, the phosphorylation at their C-terminal regions was not induced by HGF treatment. The activated JNK could directly phosphorylate R-Smads in vitro at the same sites that were phosphorylated in response to TGF-beta or HGF in vivo. Thus, the linker regions of R-Smads were the common phosphorylation sites for HGF and TGF-beta signaling pathways. The phosphorylation induced by simultaneous treatment with HGF and TGF-beta allowed R-Smads to associate with Smad4 and to translocate into the nucleus. JNK pathway involved HGF and TGF-beta-mediated infiltration potency since a JNK inhibitor SP600125 caused the reduction of invasive capacity induced by HGF and TGF-beta signals. Moreover, a combined treatment with HGF and TGF-beta led to a potent increase in plasminogen activator inhibitor type 1 transcriptional activity through Smad3 phosphorylation at the linker region. In contrast, HGF treatment reduced TGF-beta-dependent activation of p15(INK4B) promoter, in which Smad3 phosphorylation at the C-terminal region was involved. In conclusion, HGF and TGF-beta transmit the signals through JNK-mediated R-Smads phosphorylation at linker regions.