Growth hormone receptor C-terminal domains required for growth hormone-induced intracellular free Ca2+ oscillations and gene transcription
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Growth hormone receptor C-terminal domains required for growth hormone-induced intracellular free Ca2+ oscillations and gene transcription. / Billestrup, N; Bouchelouche, P; Allevato, G; Ilondo, M; Nielsen, Jens Høiriis.
I: Proceedings of the National Academy of Sciences of the United States of America, Bind 92, Nr. 7, 28.03.1995, s. 2725-9.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Growth hormone receptor C-terminal domains required for growth hormone-induced intracellular free Ca2+ oscillations and gene transcription
AU - Billestrup, N
AU - Bouchelouche, P
AU - Allevato, G
AU - Ilondo, M
AU - Nielsen, Jens Høiriis
PY - 1995/3/28
Y1 - 1995/3/28
N2 - The biological effects of growth hormone (GH) are initiated by its binding to the GH receptor (GHR) followed by association and activation of the tyrosine kinase JAK2. Here we report that GH can stimulate an increase in intracellular free Ca2+ concentration ([Ca2+]i) in cells expressing wild-type GHRs and receptor mutants lacking up to 132 amino acids of the C terminus, whereas GHRs lacking a further 52 amino acids in the C terminus are unable to induce Ca2+ signaling. The GH-induced rise in [Ca2+]i was dependent upon extracellular Ca2+ and the response consisted of GH-induced Ca2+ oscillations of varying frequency and amplitude. GH-induced transcription of the serine protease inhibitor 2.1 gene required the same C-terminal 52-amino acid domain of the receptor as for Ca2+ signaling. Mutation of the four proline residues in the conserved box 1 region of the GHR, which is responsible for binding and activation of JAK2 kinase, completely abolished GH-induced gene transcription but did not affect the GH-induced rise in [Ca2+]i. The Ca2+ channel blocker verapamil prevented GH-induced Ca2+ signaling as well as GH-induced gene transcription in cells expressing endogenous GHRs. These findings indicate that the GHR can initiate two independent signaling pathways, one requiring the box 1 region and the other requiring the region between amino acids 454 and 506, and suggest that both of these pathways are required for GH-induced gene transcription.
AB - The biological effects of growth hormone (GH) are initiated by its binding to the GH receptor (GHR) followed by association and activation of the tyrosine kinase JAK2. Here we report that GH can stimulate an increase in intracellular free Ca2+ concentration ([Ca2+]i) in cells expressing wild-type GHRs and receptor mutants lacking up to 132 amino acids of the C terminus, whereas GHRs lacking a further 52 amino acids in the C terminus are unable to induce Ca2+ signaling. The GH-induced rise in [Ca2+]i was dependent upon extracellular Ca2+ and the response consisted of GH-induced Ca2+ oscillations of varying frequency and amplitude. GH-induced transcription of the serine protease inhibitor 2.1 gene required the same C-terminal 52-amino acid domain of the receptor as for Ca2+ signaling. Mutation of the four proline residues in the conserved box 1 region of the GHR, which is responsible for binding and activation of JAK2 kinase, completely abolished GH-induced gene transcription but did not affect the GH-induced rise in [Ca2+]i. The Ca2+ channel blocker verapamil prevented GH-induced Ca2+ signaling as well as GH-induced gene transcription in cells expressing endogenous GHRs. These findings indicate that the GHR can initiate two independent signaling pathways, one requiring the box 1 region and the other requiring the region between amino acids 454 and 506, and suggest that both of these pathways are required for GH-induced gene transcription.
KW - Amino Acid Sequence
KW - Animals
KW - CHO Cells
KW - Calcium
KW - Cell Nucleus
KW - Chloramphenicol O-Acetyltransferase
KW - Conserved Sequence
KW - Cricetinae
KW - Growth Hormone
KW - Humans
KW - Insulin
KW - Janus Kinase 2
KW - Kinetics
KW - Mutagenesis, Site-Directed
KW - Peptide Fragments
KW - Polymerase Chain Reaction
KW - Proline
KW - Protein-Tyrosine Kinases
KW - Proto-Oncogene Proteins
KW - Receptors, Somatotropin
KW - Sequence Deletion
KW - Signal Transduction
KW - Time Factors
KW - Transcription, Genetic
KW - Transfection
KW - Verapamil
M3 - Journal article
C2 - 7708714
VL - 92
SP - 2725
EP - 2729
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 7
ER -
ID: 47973216