The GH receptor and signal transduction.
The primary structure of the growth hormone (GH) receptor in rabbits and humans determined by complementary DNA cloning revealed a single membrane-spanning protein of approximately 620 amino acids. A binding protein (bp) specific for GH has been identified in the serum of a number of species. In rabbits and man, a single 4.5-kb transcript has been identified that encodes the full-length receptor. In rats and mice, however, a smaller transcript produced by alternative splicing has been reported which is specific for the GHbp. Recently, the X-ray crystallographic structure of GH and its receptor have clearly shown the formation of an unusual homodimer, consisting of one molecule of GH and two molecules of hGHbp. Formation of the GH dimer is a necessary prerequisite for biological activity. The transcriptional activity of wild-type and mutant forms of GH receptor has been determined by co-transfecting the promoter of a GH-responsive gene, coupled to CAT along with the receptor cDNA. A 25-amino acid region near the transmembrane domain has been shown to be important for functional activity, although 8 amino acids (known as Box 1), rich in prolines, is essential. Alanine scanning mutagenesis has revealed that individual substitution of each residue is without effect, while the replacement of the last 2 or all 4 of the prolines abolishes activity. Finally, GH has been shown to induce rapid tyrosine phosphorylation of several proteins in cells expressing the receptor, one of which has recently been identified as the kinase JAK2 and another as MAP kinase.(ABSTRACT TRUNCATED AT 250 WORDS)
Kelly
P A
PA
INSERM Unité 344-Endocrinologie, Moléculaire, Faculté de Médecine Necker, Paris, France.
Goujon
L
L
Sotiropoulos
A
A
Dinerstein
H
H
Esposito
N
N
Edery
M
M
Finidori
J
J
Postel-Vinay
M C
MC
D000818:Animals; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D005810:Multigene Family; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011817:Rabbits; D018121:Receptors, Cytokine / Q000235:genetics; D011981:Receptors, Prolactin / Q000235:genetics; D011986:Receptors, Somatotropin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D018121:Receptors, Cytokine; D011981:Receptors, Prolactin; D011986:Receptors, Somatotropin; D014157:Transcription Factors; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases