title: Functional interaction of common gamma-chain and growth hormone receptor signaling apparatus.
abstract: 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 gamma-chain (gammac) in GHR signaling using EBV-transformed lymphocytes from healthy subjects and gammac-negative X-SCID patients. We demonstrated that the proliferative response to GH stimulation of the B cell lines of gammac-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 gammac-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 gammac abnormal biochemical and functional events were restored resulting in nuclear translocation of STAT5. Confocal experiments revealed that GHR and gammac were colocalized on the cell membrane. Our study demonstrates the existence of a previously unappreciated relationship between GHR-signaling pathway and gammac, 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.
authors.affiliation: Department of Pediatrics, Federico II University, Naples, Italy.
authors.forename: Marsilio
authors.initials: M
authors.lastname: Adriani
authors.forename: Corrado
authors.initials: C
authors.lastname: Garbi
authors.forename: Giada
authors.initials: G
authors.lastname: Amodio
authors.forename: Ilaria
authors.initials: I
authors.lastname: Russo
authors.forename: Marica
authors.initials: M
authors.lastname: Giovannini
authors.forename: Stefania
authors.initials: S
authors.lastname: Amorosi
authors.forename: Eliana
authors.initials: E
authors.lastname: Matrecano
authors.forename: Elena
authors.initials: E
authors.lastname: Cosentini
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
authors.forename: Claudio
authors.initials: C
authors.lastname: Pignata
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D002460:Cell Line; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002472:Cell Transformation, Viral / Q000235:genetics; D002478:Cells, Cultured; D041321:Chromosomes, Human, X / Q000235:genetics; D008040:Genetic Linkage; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011986:Receptors, Somatotropin / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D053631:Interleukin Receptor Common gamma Subunit; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D014443:Tyrosine