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J. Biol. Chem., Vol. 278, Issue 35, 32929-32935, August 29, 2003

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Threonine 391 Phosphorylation of the Human Prolactin Receptor Mediates a Novel Interaction with 14-3-3 Proteins^*,

Monilola A. Olayioye  , Mark A. Guthridge ¶, Frank C. Stomski ¶, Angel F. Lopez ¶, Jane E. Visvader  and Geoffrey J. Lindeman  ||

From the Walter and Eliza Hall Institute of Medical Research and Bone Marrow Research Laboratories, 1G Royal Parade, Victoria 3050, Australia and the ^¶Hanson Centre for Cancer Research, Frome Road, Adelaide, SA 5000, Australia

The prolactin receptor (PrlR) is a member of the cytokine receptor superfamily that lacks an intrinsic kinase domain and relies on the cytoplasmic Jak tyrosine kinases to transduce signals. Prolactin-induced Jak2 activation and consequent tyrosine phosphorylation of the receptor and downstream signaling molecules have been studied, but phosphorylation of the PrlR on serine or threonine residues has not been reported. Here we describe a novel interaction between the PrlR and the phosphoserine/phosphothreonine-binding 14-3-3 proteins. This association is mediated by the KCST³⁹¹WP motif, which occurs in the major functional isoform of the human receptor and is conserved among a wide variety of species. Mutagenesis of threonine 391 to alanine significantly impaired 14-3-3 binding to the PrlR in both glutathione S-transferase pulldown and coimmunoprecipitation assays. In breast carcinoma and mouse mammary epithelial cell lines, the endogenous receptor was found to associate with glutathione S-transferase-14-3-3 proteins independent of prolactin stimulation. A phospho-specific peptide antibody was generated and used to demonstrate phosphorylation of Thr³⁹¹ in vivo. Phosphorylation of this site was found to be sensitive to okadaic acid, a specific inhibitor of serine/threonine protein phosphatases. Interestingly, the T391A PrlR mutant exhibited increased basal and prolactin-induced tyrosine phosphorylation compared with the wild-type receptor. This was accompanied by a ligand-induced increase in protein kinase B and Erk activation but not that of Stat5a. Phosphorylation of the receptor on Thr³⁹¹ may therefore provide a new mechanism by which prolactin signaling is attenuated.

Received for publication, March 21, 2003 , and in revised form, June 20, 2003.

^* This work was funded by the Victorian Breast Cancer Research Consortium. 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.

The on-line version of this article (available at http://www.jbc.org) contains two supplementary figures.

Supported by a long-term European Molecular Biology fellowship.

^|| To whom correspondence should be addressed. Tel.: 61-3-9342-2165; Fax: 61-3-9347-0852; E-mail: lindeman{at}wehi.edu.au.

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