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J. Biol. Chem., Vol. 279, Issue 20, 20898-20905, May 14, 2004

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Caveolar and Lipid Raft Localization of the Growth Hormone Receptor and Its Signaling Elements

IMPACT ON GROWTH HORMONE SIGNALING^*

Ning Yang, Yao Huang, Jing Jiang, and Stuart J. Frank¶||

From the Department of Cell Biology and the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294 and the ^¶Endocrinology Section, Medical Service, Veterans Affairs Medical Center, Birmingham, Alabama 35233

The growth hormone receptor (GHR) is a cell surface receptor that mediates the somatogenic and metabolic effects of the growth hormone (GH). GHR signaling is transduced via the receptor-associated cytoplasmic tyrosine kinase called Janus protein kinase 2 (JAK2). The major intracellular signaling systems activated by JAK2 in response to GH include the signal transducer and activator of transcription (STAT) 5 and extracellular signal-regulated kinase (ERK)-1 and -2 pathways. In this report, we investigate the role of cholesterol-rich plasma membrane microdomains (caveolae and lipid rafts) in GH signaling. By subcellular fractionation of the GH-responsive 3T3-F442A murine preadipocyte, we found dramatic enrichment (6.7-fold) of plasma membrane GHR in the caveolae membranes (CM). JAK2 was also represented in the CM fraction, but was less enriched (2.5-fold) than GHR. ERK1/2 and the important ERK pathway upstream small adaptor protein, Grb2 (growth factor receptor-bound protein 2), were also enriched in caveolae (2.3- and 8.3-fold, respectively), but STAT5 was barely detected in the same fraction. Correspondingly, GH-induced tyrosine-phosphorylated GHR, JAK2, and ERK1/2 were highly represented in the CM fraction, whereas tyrosine-phosphorylated STAT5 was enriched in the non-membranous fraction of the post-nuclear supernatant. Additionally, GH induced further accumulation of GHR, Grb2, and SHC proteins in the CM fraction. Interestingly, treatment of the cells with the caveolae-disrupting agent, methyl--cyclodextrin (mCD), selectively inhibited GH-induced ERK1/2 activation but not STAT5 phosphorylation; repletion of cholesterol in mCD-treated cells restored GH-induced ERK activation. Comparison of 3T3-F442A cells with the GHR-expressing human IM-9 lymphoblasts revealed similar enrichment of GHR in the lipid raft fraction of IM-9 as in the CM fraction of 3T3-F442A, but there were dramatic differences in the ERKs and Grb2. The IM-9 cell, in which ERKs are not activated by GH, displayed no enrichment of ERKs and Grb2 in the lipid raft fraction. Our results suggest that localization of GHRs in the CM fraction of the plasma membrane plays important roles in signaling.

Received for publication, January 20, 2004 , and in revised form, February 25, 2004.

^* This work was supported by National Institutes of Health Grant DK58259 (to S. J. F.) and, in part, by National Institutes of Health Grant DK46395 (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.

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

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