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Submitted on February 20, 2002
Accepted on July 16, 2002
1 Endocrinology-Reproductive Physiology Program, Department of Comparative Biosciences, University of Wisconsin-Madison, WI 53706, Department of Cell Biology, University Medical Center Utrecht and Institute of Biomembranes, Heidelberglaan 100, AZU-G02.525, 3584 CX Utrecht, The Netherlands.
* To whom correspondence should be addressed. E-mail: schulerl{at}svm.vetmed.wisc.edu.
PRL regulates a variety of physiological processes, including mammary gland growth and differentiation, modulation of behavior, and immune function. A long PRL receptor (lPRLR) and short (sPRLR) isoform were identified in ruminants and rodents, which differ in their distal cytoplasmic domains and possess markedly distinct signaling capacities. Here we compared endocytosis of the bovine isoforms, and found that the lPRLR internalized faster than the sPRLR, which would contribute to short-term down-regulation of lPRLR signaling at targets expressing both isoforms. Multiple motifs were required to mediate internalization of the lPRLR, including a phenylalanine (F290) plus a nearby dileucine, and three dileucines proximal to aa 272. This is different from the closely related GHR that requires only the phenylalanine-containing motif for endocytosis. Truncated lPRLR (cT272), which is the same length as the sPRLR and contained the proximal three dileucines, internalized at the same rate as the full-length lPRLR. Finally, the two dileucines shared by the sPRLR were able to mediate similar endocytic pathways as the lPRLR, as revealed by overexpression of mutant dynamin and clathrin hub, despite the slower rate. These studies define the basis of cellular trafficking of PRLR isoforms, and increase our understanding of control of target cell responsiveness by PRL.
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