title: Krüppel-like factor 5 incorporates into the β-catenin/TCF complex in response to LPA in colon cancer cells.
abstract: 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 250-300kDa 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.
authors: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors: Leilei
authors: L
authors: Guo
authors: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors: Peijian
authors: P
authors: He
authors: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors: Yi Ran
authors: YR
authors: No
authors: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Winship Cancer Institute, Emory University, Atlanta, GA, USA. Electronic address: ccyun@emory.edu.
authors: C Chris
authors: CC
authors: Yun
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D010766:Phosphorylation; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D008246:Lysophospholipids; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C032881:lysophosphatidic acid
keywords: Colon cancer; KLF5; LPA; Phosphorylation; β-catenin