Krüppel-like factor 5 incorporates into the β-catenin/TCF complex in response to LPA in colon cancer cells.
Krüppel-like factor 5 incorporates into the β-catenin/TCF complex in response to LPA in colon cancer cells.
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DOI：
10.1016/j.cellsig.2015.02.005
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发表时间：
2015-05
影响因子：
4.8
通讯作者：
Yun CC
中科院分区：
文献类型：
--
作者：
Guo L;He P;No YR;Yun CC
溶血磷脂酸(LPA)是一种简单的磷脂，对包括结肠癌细胞在内的多种细胞都有很强的促有丝分裂作用。LPA通过激活β-catenin或Krüppel-like factor5(KLF5)来刺激结肠癌细胞的增殖，但这两种转录因子之间的功能关系尚不清楚。因此，我们试图探讨LPA激活β-连环蛋白的机制以及KLF5在LPA调节β-连环蛋白中的作用。我们发现Lpa和WNT3在HCT116细胞中相加地激活了β-catenin/Tcf(T细胞因子)报告活性。除了在血清9处磷酸化糖原合成酶激酶3β(β)外，LPA还导致β-连环蛋白在血清552和血清675处磷酸化。Ser552和Ser675突变抑制脂蛋白A诱导的β-catenin/Tcf转录活性。敲除KLF5可显著减弱LPA对β-catenin/Tcf报告活性的激活，但不影响WNT3的活性。然而，LPA对β-连环蛋白的核聚集不受KLF5基因敲除的影响。β-Catenin、Tcf和KLF5存在于一个250-300 kDa的大分子复合体中，并且它们的存在被LPA增强。LPA模拟了β-连环蛋白与TCF4的相互作用，缺失KLF5会降低β-连环蛋白-TCF4的结合和转录活性。综上所述，LPA通过多种途径激活β-连环蛋白，包括β-3和β-连环蛋白的磷酸化，以及增强TCF4与TCF4的相互作用。KLF5通过增加β-连环蛋白-TCF4的相互作用，在β-连环蛋白激活过程中发挥关键作用。
Lysophosphatidic acid (LPA) is a simple phospholipid with potent mitogenic effects on various cells including colon cancer cells. LPA stimulates proliferation of colon cancer cells by activation of β-catenin or Krüppel-like factor 5 (KLF5), but the functional relationship between these two transcription factors is not clear. Hence, we sought to investigate the mechanism of β-catenin activation by LPA and the role of KLF5 in the regulation of β-catenin by LPA. We found that LPA and Wnt3 additively activated the β-catenin/TCF (T cell factor) reporter activity in HCT116 cells. In addition to phosphorylating glycogen synthase kinase 3β (GSK-3β) at Ser9, LPA resulted in phosphorylation of β-catenin at Ser552 and Ser675. Mutation of Ser552 and Ser675 ablated LPA-induced β-catenin/TCF transcriptional activity. Knockdown of KLF5 significantly attenuated activation of β-catenin/TCF reporter activity by LPA but not by Wnt3. However, nuclear accumulation of β-catenin by LPA was not altered by knockdown of KLF5. β-catenin, TCF, and KLF5 were present in a 250–300 kDa macro-complex, and their presence was enhanced by LPA. LPA simulated the interaction of β-catenin with TCF4, and depletion of KLF5 decreased β-catenin-TCF4 association and the transcriptional activity. In summary, LPA activates β-catenin by multiple pathways involving phosphorylation of GSK-3 and β-catenin, and enhancing β-catenin interaction with TCF4. KLF5 plays a critical role in β-catenin activation by increasing the β-catenin-TCF4 interaction.
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影响因子：
29.4
作者：
Lin S;Wang D;Iyer S;Ghaleb AM;Shim H;Yang VW;Chun J;Yun CC
通讯作者：
Yun CC
影响因子：
11.2
作者：
McConnell BB;Bialkowska AB;Nandan MO;Ghaleb AM;Gordon FJ;Yang VW
通讯作者：
Yang VW
影响因子：
4.8
作者：
Guo, Peng;Dong, Xue-Yuan;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang
影响因子：
5.3
作者：
Lee, Sei-Jung;Leoni, Giovanna;Yun, C. Chris
通讯作者：
Yun, C. Chris
DOI：
10.1152/ajpgi.00321.2010
发表时间：
2010-11-01
影响因子：
4.5
作者：
Lin, Songbai;Lee, Sei-Jung;Yun, C. Chris
通讯作者：
Yun, C. Chris