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NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation

Oncogene volume 29, pages 2540–2549 (2010)Cite this article

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Abstract

The neurofibromatosis type 2 (NF2) tumor suppressor gene encodes merlin, a membrane/cytoskeleton protein necessary for the maintenance of contact inhibition of growth in cells. Bi-allelic inactivation of NF2 is known to cause multiple cancers in both humans and mice. However, the mechanism through which merlin exerts its tumor-suppressive function remains obscure. In this report, we show that NF2 knockout mouse embryonic fibroblasts lost contact inhibition of cell proliferation and contained significantly increased canonical Wnt signaling. Inhibition of Rac1, the activity of which is inversely regulated by NF2, through the use of a dominant-negative mutant, small hairpin RNA or a small molecule inhibitor in NF2-deficient cells, was able to suppress elevated Wnt signals as shown by reduced activity of the T-cell factor 4 (TCF4) transcription factor. Dominant-negative TCF4 or Rac1 mutant, as well as a small molecule inhibition of Wnt, were able to curb NF2 deficiency-elicited cell proliferation at the confluent state. Thus, Rac1-mediated canonical Wnt signaling is essential for the loss of contact inhibition in NF2-deficient cells.

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Acknowledgements

We thank all members of the Zheng laboratory for thought-provoking discussions. This study was supported by NIH R01 CA125658 (YZ), NIH R01 CA118032 (NR) and NIH T32 CA117846 (EEB). EEB and YN performed experiments, analyzed results and made the figures; RFH provided key reagents, NR collaborated on experimental design, EEB and YZ designed the research and wrote the paper.

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Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    E E Bosco, Y Nakai, N Ratner & Y Zheng

  2. Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    R F Hennigan

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  1. E E Bosco
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  2. Y Nakai
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  3. R F Hennigan
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  4. N Ratner
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  5. Y Zheng
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Correspondence to Y Zheng.

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Bosco, E., Nakai, Y., Hennigan, R. et al. NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation. Oncogene 29, 2540–2549 (2010). https://doi.org/10.1038/onc.2010.20

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