Linda Schuler
Prolactin Receptors, Signaling, and Processing

The prolactin receptor is a member of the cytokine receptor superfamily. Like other members of that family, it has a single transmembrane domain, and no intrinsic signaling activity. Several receptor isoforms, differing in cytoplasmic domains, mediate the actions of prolactin and related hormones at their targets. Those with truncated cytoplasmic domains have limited ability to transduce signal. Target tissues differ in total amount of receptor, as well as relative levels of the different receptor isoforms.

Despite recent advances in our understanding of the interactions of these hormones with their receptors and signaling processes, relatively little is known about the fate of the ligand and receptor after their interaction at the plasma membrane, the mechanisms which mediate these processes, and the relationship to hormone action. We have found that the isoform with a full length cytoplasmic domain is internalized more rapidly, resulting in a preponderance of the short isoform at the surface, contributing to signal down-regulation.

We are currently focusing on the pathways whereby these receptors are internalized, including differences in constitutive and ligand-stimulated internalization as well as that employed by the different isoforms, and identifying the mechanisms that lead to different outcomes. These studies have important implications for modulation of the target tissue response and therefore disease progression.

Publications in this area:

Schuler, L.A., R.M. Nagel, J. Gao, N.D. Horseman and M.A. Kessler. Prolactin receptor heterogeneity in fetal and maternal tissues, Endocrinology 138:3187-3194, 1997. [Abstract]

Bignon, C., N. Binart, C. Ormandy, L.A. Schuler, P.A. Kelly and J. Djiane. Long and short forms of the ovine prolactin receptors: cDNA cloning and genomic analysis reveal alternative splicing mechanisms in ruminants and in rodents. J. Mol. Endocrinol. 19:109-120, 1997. [Abstract]
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Schuler, L.A., J-C. Lu and J.L. Brockman Prolactin receptor heterogeneity:  Processing and signaling of the long and short isoforms during development.  Biochem. Soc. Trans. 29:52-56, 2001.

Lu, J.-C., Scott, P., Strous, G.J., and L.A. Schuler. Multiple internalization motifs differentially used by prolactin receptor isoforms mediate similar endocytic pathways. Mol. Endocrinol., 16:2515-2527, 2002. [Abstract]

Lu, J.-C, T.M. Piazza, and L.A. Schuler. Proteasomes mediate prolactin-induced receptor down-regulation and fragment generation in breast cancer cells. J. Biol. Chem. 280:33909-33916, 2005. [Abstract]

Piazza, T.M., J.-C. Lu, K.C. Carver, and L.A. Schuler. Prolactin activation of srcs accelerates receptor internalization, modulating trafficking and signaling in breast cancer cells, submitted