Identification of a region critical for proteolysis of the human growth hormone receptor.
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.
Conte
Françoise
F
Centre de Recherche sur la Croissance (CRC), Pavillon Leriche, Hôpital Purpan, Place du Dr. Baylac, Toulouse cedex, 31059, France. crc@chu-toulouse.fr
Salles
Jean Pierre
JP
Raynal
Patrick
P
Fernandez
Laurent
L
Molinas
Catherine
C
Tauber
Maïté
M
Bieth
Eric
E
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
D002352:Carrier Proteins; D011986:Receptors, Somatotropin; D013006:Growth Hormone; D010447:Peptide Hydrolases; D013755:Tetradecanoylphorbol Acetate; C051815:somatotropin-binding protein