title: Identification of a region critical for proteolysis of the human growth hormone receptor.
abstract: Release of soluble growth hormone binding protein (GHBP) corresponding to the extracellular domain of the GH receptor (GHR) occurs via distinct mechanisms depending on species. In human, proteolysis of full length GHR results in liberation of GHBP into the extracellular medium. A putative protease responsive for GHR cleavage has been identified, however, the residues involved are still unknown. In this study, using the mutational approach to the extracellular domain of the human GHR, we demonstrated that deletion of three residues located close to the transmembrane domain abolishes constitutive GHBP shedding without change in cellular GH binding. Deletion also significantly decreased the phorbol 12-myristate 13-acetate (PMA)-induced release of GHBP and the accumulation of membrane-anchored remnant proteins. Taken together, these results suggest that integrity of the juxtamembrane region of GHR is necessary for its biochemical cleavage and that a common mechanism is involved in constitutive and PMA-induced shedding.
authors.affiliation: Centre de Recherche sur la Croissance (CRC), Pavillon Leriche, Hôpital Purpan, Place du Dr. Baylac, Toulouse cedex, 31059, France. crc@chu-toulouse.fr
authors.forename: Françoise
authors.initials: F
authors.lastname: Conte
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Salles
authors.forename: Patrick
authors.initials: P
authors.lastname: Raynal
authors.forename: Laurent
authors.initials: L
authors.lastname: Fernandez
authors.forename: Catherine
authors.initials: C
authors.lastname: Molinas
authors.forename: Maïté
authors.initials: M
authors.lastname: Tauber
authors.forename: Eric
authors.initials: E
authors.lastname: Bieth
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010447:Peptide Hydrolases / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000502:physiology; D011986:Receptors, Somatotropin / Q000235:genetics* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D011986:Receptors, Somatotropin; D013006:Growth Hormone; D010447:Peptide Hydrolases; D013755:Tetradecanoylphorbol Acetate; C051815:somatotropin-binding protein