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J. Biol. Chem. 275 (9): 6295-6301

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

J Biol Chem, Vol. 275, Issue 9, 6295-6301, March 3, 2000

Functional Heterodimerization of Prolactin and Growth Hormone Receptors by Ovine Placental Lactogen*

Asael HermanDagger §, Christophe Bignon§, Nathalie Daniel, Jeanne Grosclaude||, Arieh GertlerDagger **, and Jean Djiane

From the Dagger  Institute of Biochemistry, Food Science and Nutrition, Faculty of Agriculture, The Hebrew University of Jerusalem, Rehovot 76100, Israel and the  Unite d'Endocrinologie Moleculaire and || Unite de Virologie et Immunologie Moleculaire, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas, France

Although homo- or heterodimerization are common mechanisms for activation of cytokine receptors, cross-talk between two distinct receptors in this superfamily has been never shown. Here we show a physiologically relevant example indicating that such an interaction does occurs, thus raising the hypothesis that heterodimerization between distinct cytokine receptors may be a novel mechanism contributing to the diversity of cytokine signaling. These findings were documented using both surface plasmon resonance and gel filtration experiments and show that ovine placental lactogen (PL) heterodimerizes the extracellular domains (ECDs) of ruminant growth hormone receptor (GHR) and prolactin receptor (PRLR). We also show that PL or PL analogues that exhibit little or no activity in cells transfected with PRLRs and no activity in cells transfected with ovine GHRs exhibit largely enhanced activity in cells cotransfected with both PRLRs and GHRs. Furthermore, chimeric receptors consisting of cytosolic and transmembrane part of ovine GHR or ovine PRLR and ECDs of human granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) alpha  or beta  were constructed. Upon transfection into Chinese hamster ovary cells along with reporter luciferase gene and stimulation by GM-CSF, a significant increase in luciferase activity occurred when GM-CSFR-alpha -PRLR and GM-CSFR-beta -GHR or GM-CSFR-alpha -GHR and GM-CSRR-beta -PRLR were cotransfected. In conclusion, we show that ovine PL is capable of functional heterodimerization of GHR and PRLR and that when their cytosolic parts, coupled to the ECD of GM-CSF receptors, are heterodimerized by GM-CSF, they are capable of transducing biological signal.

* This work was supported by USA-Israel Binational Science Foundation Grant 9500327 and USA-Israel Binational Agricultural and Development Fund Grant US-2643-95.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

** To whom the correspondence should be addressed: Inst. of Biochemistry, Food Science and Nutrition, Faculty of Agriculture, The Hebrew University of Jerusalem, POB 12, Rehovot 76100, Israel. Tel.: 972-8-948-9006; Fax: 972-8-947-6189; E-mail: gertler@agri.huji.ac.il.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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