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Nuclear Translocation and Retention of Growth Hormone

Centre National de la Recherche Scientifique Unité Mixte de Recherche 5123 Physiologie Energetique Cellulaire et Moléculaire (H.C.M., M.R., A.A., G.M.), Université Claude Bernard-Lyon-I, 69622 France; Department of Physiology (J.K., J.T.), University of Göteborg, 43183 Göteborg, Sweden; Hagedorn Research Laboratory (N.B.), 2820 Gentofte, Denmark; Laboratory DyOGen (Y.U.), Université Joseph Fourier, 38706 Grenoble, France; and Institute of Molecular and Cell Biology (P.E.L.), National University of Singapore, Singapore 117609, Republic of Singapore

Address all correspondence and requests for reprints to: Peter E. Lobie, Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Republic of Singapore. E-mail: mcbpel{at}imcb.nus.edu.sg

We have previously demonstrated that GH is subject to rapid receptor-dependent nuclear translocation. Here, we examine the importance of ligand activation of the GH-receptor (GHR)-associated Janus kinase (JAK) 2 and receptor dimerization for hormone internalization and nuclear translocation by use of cells stably transfected with cDNA for the GHR. Staurosporine and herbimycin A treatment of cells did not affect the ability of GH to internalize but resulted in increased nuclear accumulation of hormone. Similarly, receptor mutations, which prevent the association and activation of JAK2, did not affect the ability of the hormone to internalize or translocate to the nucleus but resulted in increased nuclear accumulation of GH. These results were observed both by nuclear isolation and confocal laser scanning microscopy. Staurosporine treatment of cells in which human GH (hGH) was targeted to the cytoplasm (removal of secretion sequence) or to the nucleus (addition of the nuclear localization sequence of SV40 large T antigen) resulted in preferential accumulation of hGH in the nucleus. We further investigated the requirement of receptor dimerization for GH nuclear translocation using the non-receptor-dimerizing hGH antagonist, hGH-G120R, conjugated to fluorescein isothiocyanate. Confocal laser scanning microscopy demonstrated efficient internalization of both hGH and hGH-G120R but lack of nuclear translocation of hGH-G120R. Thus, we conclude that activation of JAK2 kinase and the subsequent tyrosine phosphorylation is not required for nuclear translocation of GH but is pivotal for the removal of the hormone from the nucleus, and that GH translocates into the nucleus in a GHR dimerized-dependent fashion.

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