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Functional Interaction of Common -Chain and Growth Hormone Receptor Signaling Apparatus¹

Marsilio Adriani^*, Corrado Garbi, Giada Amodio^*, Ilaria Russo^*, Marica Giovannini^*, Stefania Amorosi^*, Eliana Matrecano^*, Elena Cosentini, Fabio Candotti and Claudio Pignata^2,*

^* Department of Pediatrics, Department of Cellular and Molecular Biology and Pathology, and Immunohematology Unit, "Federico II" University, Naples, Italy; and Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892

We previously reported on an X-linked SCID (X-SCID) patient, who also had peripheral growth hormone (GH) hyporesponsiveness and abnormalities of the protein phosphorylation events following GH receptor (GHR) stimulation. In the present study, we examined a potential role of common cytokine receptor -chain (_c) in GHR signaling using EBV-transformed lymphocytes from healthy subjects and _c-negative X-SCID patients. We demonstrated that the proliferative response to GH stimulation of the B cell lines of _c-negative patients was impaired despite a comparable cellular expression of GHR molecules to controls. In patients, after GH stimulation, no phosphorylation of STAT5 was observed. In addition, the molecule localization through confocal microscopy revealed that in B cell lines of patients no nuclear translocation of STAT5b following GH stimulation occurred differently from controls. Biochemical analysis of the nuclear extracts of _c-negative cell lines provided further evidence that the amount of STAT5b and its phosphorylated form did not increase following GH stimulation. In patients, cells reconstituted with wild-type _c abnormal biochemical and functional events were restored resulting in nuclear translocation of STAT5. Confocal experiments revealed that GHR and _c were colocalized on the cell membrane. Our study demonstrates the existence of a previously unappreciated relationship between GHR-signaling pathway and _c, which is required for the activation of STAT5b in B cell lines. These data also confirm that growth failure in X-SCID is primarily related to the genetic alteration of the IL2RG gene.

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.

¹ This work was supported by Ministero della Salute-Roma and Regione Campania, Legge 502 and Ministero dell’Università e della Ricerca Scìentifica e Tecnologica, Progetto di Rilevante Interesse Nazionale and by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health.

² Address correspondence and reprint request to Dr. Claudio Pignata, Department of Pediatrics, Unit of Immunology, "Federico II" University, Via S. Pansini 5-80131, Naples, Italy. E-mail address: pignata{at}unina.it

³ Abbreviations used in this paper: X-SCID, X-linked SCID; _c, common cytokine receptor -chain; GH, growth hormone; GHR, GH receptor; IGF, insulin-like growth factor; rGH, recombinant human GH; BCL, lymphoblastoid cell line; WT, wild type.