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Vol. 17, Issue 7, 2963-2975, July 2006

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Phosphoinositide-3 Kinase–Rac1–c-Jun NH₂-terminal Kinase Signaling Mediates Collagen I–induced Cell Scattering and Up-Regulation of N-Cadherin Expression in Mouse Mammary Epithelial Cells

Yasushi Shintani^*, Margaret J. Wheelock^*,,,,||,¶, and Keith R. Johnson^*,,,,||,¶

Departments of *Oral Biology, Biochemistry and Molecular Biology, Genetics, Cell Biology, and Anatomy, and Pathology and Microbiology, ^||Eppley Institute for Research in Cancer and Allied Diseases, and ^¶Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-7696

Submitted December 13, 2005; Revised March 14, 2006; Accepted April 10, 2006
Monitoring Editor: Jean Schwarzbauer

During epithelial-to-mesenchymal transitions (EMTs), cells must change their interactions with one another and with their extracellular matrix in a synchronized manner. To characterize signaling pathways cells use to coordinate these changes, we used NMuMG mammary epithelial cells. We showed that these cells become fibroblastic and scattered, with increased N-cadherin expression when cultured on collagen I. Rac1 and c-Jun NH₂-terminal kinase (JNK) were activated when cells were plated on collagen I, and dominant inhibitory Rac1 (RacN17) or inhibition of JNK signaling prevented collagen I–induced morphological changes and N-cadherin up-regulation. Furthermore, inhibiting phosphoinositide-3 kinase (PI3K) activity prevented Rac1 and JNK activation as well as collagen I–induced N-cadherin up-regulation. These data implicate PI3K–Rac1–JNK signaling in collagen I–induced changes in NMuMG cells. To establish a role for N-cadherin in collagen I–induced cell scattering, we generated N-cadherin overexpressing and knockdown NMuMG cells and showed that knocking down N-cadherin expression prevented collagen I–induced morphological changes. Motility assays showed that cells overexpressing N-cadherin were significantly more motile than mock-transfected cells and that N-cadherin-mediated motility was collagen I dependent. In addition, we showed that cord formation and branching in three-dimensional culture (EMT-dependent events) required N-cadherin expression and PI3K–Rac1–JNK signaling.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Margaret J. Wheelock ( mwheelock{at}unmc.edu)

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