Enhancement of TGF-β-induced Smad3 activity by c-Abl-mediated tyrosine phosphorylation of its coactivator SKI-interacting protein (SKIP).
Enhancement of TGF-β-induced Smad3 activity by c-Abl-mediated tyrosine phosphorylation of its coactivator SKI-interacting protein (SKIP).
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c-Abl 介导的共激活剂 SKI 相互作用蛋白 (SKIP) 酪氨酸磷酸化增强 TGF-β 诱导的 Smad3 活性。
DOI：
10.1016/j.bbrc.2017.06.163
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发表时间：
2017
影响因子：
3.1
通讯作者：
Yamaguchi N
中科院分区：
文献类型：
--
作者：
Kuki K;Yamaguchi N;Iwasawa S;Takakura Y;Aoyama K;Yuki R;Nakayama Y;Kuga T;Hashimoto Y;Tomonaga T;Yamaguchi N
c-Abl是一种非受体型酪氨酸激酶，在细胞增殖、迁移、凋亡和纤维化中起重要作用。此外，虽然c-Abl参与转化生长因子-β（TGF-β）信号传导，但其在TGF-β信号传导中的分子功能尚未完全了解。在这里，我们发现c-Abl磷酸化SKI相互作用蛋白（SKIP），转录因子Smad 3的核辅因子。c-Abl抑制剂伊马替尼抑制TGF-β诱导的Smad 3靶点表达以及SKIP/Smad 3相互作用。TGF-β刺激诱导SKIP的酪氨酸磷酸化，并且这种磷酸化被伊马替尼抑制。SKIP中的Tyr 292、Tyr 430和Tyr 433残基参与c-Abl介导的磷酸化。SKIP中Tyr 292的拟磷酸化谷氨酸取代增强了TGF-β诱导的SKIP/Smad 3相互作用，而其磷酸化死亡的苯丙氨酸取代减弱了TGF-β诱导的SKIP/Smad 3相互作用。此外，磷酸模拟突变体SKIP增强Smad 3的转录活性。综上所述，这些结果表明，c-Abl主要在Tyr 292处磷酸化SKIP，并促进SKIP/Smad 3相互作用以完全激活TGF-β/Smad 3信号传导。
c-Abl is a non-receptor-type tyrosine kinase that plays an important role in cell proliferation, migration, apoptosis, and fibrosis. Furthermore, although c-Abl is involved in transforming growth factor-β (TGF-β) signaling, its molecular functions in TGF-β signaling are not fully understood. Here, we found that c-Abl phosphorylates SKI-interacting protein (SKIP), a nuclear cofactor of the transcription factor Smad3. The c-Abl inhibitor imatinib suppressed TGF-β-induced expression of Smad3 targets as well as SKIP/Smad3 interaction. TGF-β-stimulation induced tyrosine phosphorylation of SKIP, and this phosphorylation was suppressed by imatinib. Tyr292, Tyr430, and Tyr433residues in SKIP were shown to be involved in c-Abl-mediated phosphorylation. Phosphomimetic glutamic acid substitution at Tyr292in SKIP enhanced, whereas its phospho-dead phenylalanine substitution attenuated TGF-β-induced SKIP/Smad3 interaction. Moreover, the phosphomimetic mutant of SKIP augmented transcriptional activity of Smad3. Taken together, these results suggest that c-Abl phosphorylates SKIP mainly at Tyr292and promotes SKIP/Smad3 interaction for the full activation of TGF-β/Smad3 signaling.