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J. Biol. Chem., Vol. 280, Issue 40, 33909-33916, October 7, 2005

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Proteasomes Mediate Prolactin-induced Receptor Down-regulation and Fragment Generation in Breast Cancer Cells^*

Juu-Chin Lu12, Timothy M. Piazza¶1, and Linda A. Schuler¶3

From the Department of Comparative Biosciences, Endocrinology-Reproductive Physiology Program, and ^¶Comparative Biomedical Sciences Program, University of Wisconsin-Madison, Wisconsin 53706

Prolactin regulates a variety of physiological processes, including mammary gland growth and differentiation, and recent findings support an important role in breast cancer development and progression. However, little is known about the trafficking of its receptor, a member of the cytokine receptor superfamily. In the present study, we examined the effect of ligand on the endogenous "long" isoform of the prolactin receptor in breast cancer cells. We found that prolactin caused rapid and prolonged down-regulation of this receptor. The prolactin-induced increase in degradation was blocked by inhibitors of both proteasomes and lysosomes. However, the ubiquitin-conjugating system was not required for internalization. Prolactin also resulted in the concomitant appearance of a cell-associated prolactin receptor fragment containing the extracellular domain. This latter process required proteasomal, but not metalloprotease, activity, distinguishing it from ectodomain "shedding" of other membrane receptors, which are secreted as binding proteins. The prolactin receptor fragment was labeled by surface biotinylation and independent of protein synthesis. Together, these data indicated that prolactin binding initiates limited proteasomal cleavage of its receptor, generating a cell-associated fragment containing the extracellular domain. Our findings described a new potential mediator of prolactin action and a novel mechanism whereby proteasomes modulate cellular processes.

Received for publication, July 25, 2005

^* This work was supported in part by National Institutes of Health R01 CA78312 and R01 DK62783, the University of Wisconsin Center for Women's Health and Women's Health Research and the University of Wisconsin School of Veterinary Medicine. 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 Both authors contributed equally to this work.

² Present address: Division of Endocrinology and Metabolism, Dept. of Medicine, University of California, San Diego, CA 92093.

³ To whom correspondence should be addressed: Dept. of Comparative Biosciences, University of Wisconsin, 2015 Linden Dr., Madison, WI 53706. Tel.: 608-263-9825; Fax: 608-263-3926; E-mail: schulerl{at}svm.vetmed.wisc.edu.

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