Identification of the LIM Protein FHL2 as a Coactivator of β-Catenin*

By Yu Wei, C. Renard, C. Labalette, Yuanfei Wu, Laurence Levy, C. Neuveut, X. Prieur, M. Flajolet, S. Prigent, M. Buendia. Journal of Biological Chemistry, 2003

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β-Catenin is a key mediator of the Wnt pathway, which plays a critical role in embryogenesis and oncogenesis. As a transcriptional activator, β-catenin binds the transcription factors, T-cell factor and lymphoid enhancer factor, and regulates gene expression in response to Wnt signaling. Abnormal activation of β-catenin has been linked to various types of cancer. In a yeast two-hybrid screen, we identified the four and a half of LIM-only protein 2 (FHL2) as a novel β-catenin-interacting protein. Here we show specific interaction of FHL2 with β-catenin, which requires the intact structure of FHL2 and armadillo repeats 1–9 of β-catenin. FHL2 cooperated with β-catenin to activate T-cell factor/lymphoid enhancer factor-dependent transcription from a synthetic reporter and the cyclin D1 and interleukin-8 promoters in kidney and colon cell lines. In contrast, coexpression of β-catenin and FHL2 had no synergistic effect on androgen receptor-mediated transcription, whereas each of these two coactivators independently stimulated AR transcriptional activity. Thus, the ability of FHL2 to stimulate the trans-activating function of β-catenin might be dependent on the promoter context. The detection of increased FHL2 expression in hepatoblastoma, a liver tumor harboring frequent β-catenin mutations, suggests that FHL2 might enforce β-catenin transactivation activity in cancer cells. These findings reveal a new function of the LIM coactivator FHL2 in transcriptional activation of Wnt-responsive genes.

Subfields: Molecular Biology

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