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J. Biol. Chem., Vol. 281, Issue 28, 19310-19319, July 14, 2006

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The Mucin Muc4 Potentiates Neuregulin Signaling by Increasing the Cell-surface Populations of ErbB2 and ErbB3^*

Melanie Funes¹, Jamie K. Miller, Cary Lai, Kermit L. Carraway, III², and Colleen Sweeney

From the University of California-Davis Cancer Center, Sacramento, California 95817 and the Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037

Mucins provide a protective barrier for epithelial surfaces, and their overexpression in tumors has been implicated in malignancy. We have previously demonstrated that Muc4, a transmembrane mucin that promotes tumor growth and metastasis, physically interacts with the ErbB2 receptor tyrosine kinase and augments receptor tyrosine phosphorylation in response to the neuregulin-1 (NRG1) growth factor. In the present study we demonstrate that Muc4 expression in A375 human melanoma cells, as well as MCF7 and T47D human breast cancer cells, enhances NRG1 signaling through the phosphatidylinositol 3-kinase pathway. In examining the mechanism underlying Muc4-potetiated ErbB2 signaling, we found that Muc4 expression markedly augments NRG1 binding to A375 cells without altering the total quantity of receptors expressed by the cells. Cell-surface protein biotinylation experiments and immunofluorescence studies suggest that Muc4 induces the relocalization of the ErbB2 and ErbB3 receptors from intracellular compartments to the plasma membrane. Moreover, Muc4 interferes with the accumulation of surface receptors within internal compartments following NRG1 treatment by suppressing the efficiency of receptor internalization. These observations suggest that transmembrane mucins can modulate receptor tyrosine kinase signaling by influencing receptor localization and trafficking and contribute to our understanding of the mechanisms by which mucins contribute to tumor growth and progression.

Received for publication, April 5, 2006 , and in revised form, May 9, 2006.

^* This work was supported in part by California Breast Cancer Research Program Grant 7KB-0085 (to C .S.) and National Institutes of Health Grant GM068994 (to K. L. C.). 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.

¹ Supported by a California Breast Cancer Research Program supplemental award (Grant 7KB-0085S).

² To whom correspondence should be addressed: University of California-Davis Cancer Center, Research Bldg. III, Rm. 1400, 4645 2nd Ave., Sacramento, CA 95817. Tel.: 916-734-0726; Fax: 916-734-0190; E-mail: klcarraway{at}ucdavis.edu.

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