Guo L, He P, No YR, Yun CC

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 ?-catenin or Krueppel-like factor 5 (KLF5), but the functional relationship between these two transcription factors is not clear. Hence, we sought to ...

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investigate the mechanism of ?-catenin activation by LPA and the role of KLF5 in the regulation of ?-catenin by LPA. We found that LPA and Wnt3 additively activated the ?-catenin/TCF (T cell factor) reporter activity in HCT116 cells. In addition to phosphorylating glycogen synthase kinase 3? (GSK-3?) at Ser9, LPA resulted in phosphorylation of ?-catenin at Ser552 and Ser675. Mutation of Ser552 and Ser675 ablated LPA-induced ?-catenin/TCF transcriptional activity. Knockdown of KLF5 significantly attenuated activation of ?-catenin/TCF reporter activity by LPA but not by Wnt3. However, nuclear accumulation of ?-catenin by LPA was not altered by knockdown of KLF5. ?-catenin, TCF, and KLF5 were present in a 250-300kDa macro-complex, and their presence was enhanced by LPA. LPA simulated the interaction of ?-catenin with TCF4, and depletion of KLF5 decreased ?-catenin-TCF4 association and the transcriptional activity. In summary, LPA activates ?-catenin by multiple pathways involving phosphorylation of GSK-3 and ?-catenin, and enhancing ?-catenin interaction with TCF4. KLF5 plays a critical role in ?-catenin activation by increasing the ?-catenin-TCF4 interaction.

Date: May. 01, 2015

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