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J. Biol. Chem., Vol. 279, Issue 42, 44093-44100, October 15, 2004

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Mammary Gland Remodeling Depends on gp130 Signaling through Stat3 and MAPK^*

Ling Zhao, Stefan Hart¶, JrGang Cheng||, J. Joseph Melenhorst**, Brian Bierie, Matthias Ernst, Colin Stewart||, Fred Schaper, Peter C. Heinrich, Axel Ullrich¶, Gertraud W. Robinson, and Lothar Hennighausen¶¶¶

From the Laboratory of Genetics and Physiology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, the ^¶Max Planck Institute for Biochemistry, Martinsried 81399, Germany, the ^||Laboratory of Cancer and Developmental Biology, NCI, National Institutes of Health, Frederick, Maryland 21702, the ^**Hematology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, the Ludwig Institute for Cancer Research, Melbourne, Vic 3050, Australia, and the Department of Biochemistry, RWTH, Aachen 52074, Germany

The interleukin-6 (IL6) family of cytokines signals through the common receptor subunit gp130, and subsequently activates Stat3, MAPK, and PI3K. Stat3 controls cell death and tissue remodeling in the mouse mammary gland during involution, which is partially induced by IL6 and LIF. However, it is not clear whether Stat3 activation is mediated solely through the gp130 pathway or also through other receptors. This question was explored in mice carrying two distinct mutations in the gp130 gene; one that resulted in the complete ablation of gp130 and one that led to the loss of Stat3 binding sites (gp130/). Deletion of gp130 specifically from mammary epithelium resulted in a complete loss of Stat3 activity and resistance to tissue remodeling comparable to that seen in the absence of Stat3. A less profound delay of mammary tissue remodeling was observed in gp130/ mice. Stat3 tyrosine and serine phosphorylation was still detected in these mice suggesting that Stat3 activation could be the result of gp130 interfacing with other receptors. Experiments in primary mammary epithelial cells and transfected COS-7 cells revealed a p44/42 MAPK and EGFR-dependent Stat3 activation. Moreover, the gp130-dependent EGFR activation was independent of EGF ligands, suggesting a cytoplasmic interaction and cross-talk between these two receptors. These experiments establish that two distinct Stat3 signaling pathways emanating from gp130 are utilized in mammary tissue.

Received for publication, December 2, 2003 , and in revised form, July 26, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Current address: Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, MD 20892.

^¶¶ To whom correspondence should be addressed: Laboratory of Genetics and Physiology, NIDDK, National Institutes of Health, Bethesda, MD 20892. E-mail: hennighausen{at}nih.gov.

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