NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation.
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.
Bosco
E E
EE
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Nakai
Y
Y
Hennigan
R F
RF
Ratner
N
N
Zheng
Y
Y
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003260:Contact Inhibition; D051379:Mice; D025581:Neurofibromin 2 / Q000172:deficiency / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000502:physiology*; D020830:rac1 GTP-Binding Protein
D025581:Neurofibromin 2; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D051153:Wnt Proteins; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein