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Molecular and Cellular Biology, August 2006, p. 6024-6036, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.02354-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Wnt-5a/Ca2+-Induced NFAT Activity Is Counteracted by Wnt-5a/Yes-Cdc42-Casein Kinase 1{alpha} Signaling in Human Mammary Epithelial Cells

Janna Dejmek,{dagger} Annette Säfholm,{dagger} Christian Kamp Nielsen, Tommy Andersson, and Karin Leandersson*

Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden

Received 9 December 2005/ Returned for modification 5 January 2006/ Accepted 17 May 2006

Wnt-5a has been shown to influence the metastatic behavior of human breast cancer cells, and the loss of Wnt-5a expression is associated with metastatic disease. We show here that NFAT1, a transcription factor connected with breast cancer metastasis, is activated by Wnt-5a through a Ca2+ signaling pathway in human breast epithelial cells. This activation was simultaneously counteracted by a Wnt-5a-induced Yes/Cdc42 signaling pathway. The observation that inhibition of the Wnt-5a/Yes/Cdc42 signal prolonged the duration of ionomycin-induced NFAT1 activation revealed the general importance of this pathway. The Wnt-5a-induced inhibition of NFAT1 did not require glycogen synthase kinase 3ß, JNK, or Pak1 activity or modulation of the cytoskeleton. Instead, we observed that Wnt-5a induced a complex formation of NFAT1/casein kinase 1{alpha}, even upon treatment with ionomycin, which was blocked upon inhibition of the Wnt-5a/Yes/Cdc42 signaling pathway. Our results explain why Wnt-5a/Ca2+-induced NFAT activity is hard to detect and suggest a novel mechanism by which Wnt-5a can suppress tumor-specific, agonist-induced NFAT activity and thus the metastatic behavior of breast cancer cells.

* Corresponding author. Mailing address: Experimental Pathology, Department of Laboratory Medicine, Lund University, U-MAS, Entrance 78, SE-205 02 Malmö, Sweden. Phone: 46 40 337768. Fax: 46 40 337353. E-mail: Karin.Leandersson{at}med.lu.se.

{dagger} J.D. and A.S. contributed equally to this study.

Molecular and Cellular Biology, August 2006, p. 6024-6036, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.02354-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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