Open AccessWnt-5a/Ca2+-Induced NFAT Activity Is Counteracted by Wnt-5a/Yes-Cdc42-Casein Kinase 1α Signaling in Human Mammary Epithelial Cells
Author(s) -
Janna Dejmek,
Annette Säfholm,
Christian Kamp Nielsen,
Tommy Andersson,
Karin Leandersson
Publication year - 2006
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.02354-05
Subject(s) - wnt signaling pathway , casein kinase 1 , biology , nfat , microbiology and biotechnology , cancer research , signal transduction , pak1 , ionomycin , kinase , transcription factor , protein kinase a , biochemistry , gene , intracellular
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 3β, JNK, or Pak1 activity or modulation of the cytoskeleton. Instead, we observed that Wnt-5a induced a complex formation of NFAT1/casein kinase 1α, 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.