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J. Biol. Chem., Vol. 280, Issue 19, 19331-19342, May 13, 2005

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Growth Hormone Receptor Is a Target for Presenilin-dependent -Secretase Cleavage^*

Jon W. Cowan, Xiangdong Wang, Ran Guan, Kai He, Jing Jiang, Gerhard Baumann¶, Roy A. Black||, Michael S. Wolfe**, and Stuart J. Frank¶¶

From the Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294, the ^¶Center for Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Medical School, and the Veterans Administration Chicago Health System, Lakeside Division, Chicago, Illinois 60611, ^||Amgen Incorporated, Seattle, Washington 98101, the ^**Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, and the Endocrinology Section, Medical Service, Veterans Affairs Medical Center, Birmingham, Alabama 35233

Growth hormone receptor (GHR) is a cytokine receptor superfamily member that binds growth hormone (GH) via its extracellular domain and signals via interaction of its cytoplasmic domain with JAK2 and other signaling molecules. GHR is a target for inducible metalloprotease-mediated cleavage in its perimembranous extracellular domain, a process that liberates the extracellular domain as the soluble GH-binding protein and leaves behind a cell-associated GHR remnant protein containing the transmembrane and cytoplasmic domains. GHR metalloproteolysis can be catalyzed by tumor necrosis factor--converting enzyme (ADAM-17) and is associated with down-modulation of GH signaling. We now study the fate of the GHR remnant protein. By anti-GHR cytoplasmic domain immunoblotting, we observed that the remnant induced in response to phorbol ester or platelet-derived growth factor has a reliable pattern of appearance and disappearance in both mouse preadipocytes endogenously expressing GHR and transfected fibroblasts expressing rabbit GHR. Lactacystin, a specific proteasome inhibitor, did not appreciably change the time course of remnant appearance or clearance but allowed detection of the GHR stub, a receptor fragment slightly smaller than the remnant but containing the C terminus of the remnant (receptor cytoplasmic domain). In contrast, MG132, another (less specific) proteasome inhibitor, strongly inhibited remnant clearance and prevented stub appearance. Inhibitors of -secretase, an aspartyl protease, also prevented the appearance of the stub, even in the presence of lactacystin, and concomitantly inhibited remnant clearance in the same fashion as MG132. In addition, mouse embryonic fibroblasts derived from presenilin 1 and 2 (PS1/2) knockouts recapitulated the -secretase inhibitor studies, as compared with their littermate controls (PS1/2 wild type). Confocal microscopy indicated that the GHR cytoplasmic domain became localized to the nucleus in a fashion dependent on PS1/2 activity. These data indicate that the GHR is subject to sequential proteolysis by metalloprotease and -secretase activities and may suggest GH-independent roles for the GHR.

Received for publication, January 18, 2005

^* This work was supported by Veterans Affairs Merit Review Awards (to S. J. F. and G. B.), National Institutes of Health Training Grant T-32 GM08111 (to J. W. C.), and in part by National Institutes of Health Grants DK46395 and DK58259 (to S. J. F.). 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.

Both authors contributed equally to this work.

^¶¶ To whom correspondence should be addressed: University of Alabama at Birmingham, 1530 3rd Ave. South, BDB 861, Birmingham, AL 35294-0012. Tel.: 205-934-9877; Fax: 205-934-4389; E-mail: sjfrank{at}uab.edu.

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