Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B
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Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B. / Stofega, M R; Herrington, J; Billestrup, Nils; Carter-Su, C.
I: Molecular endocrinology (Baltimore, Md.), Bind 14, Nr. 9, 09.2000, s. 1338-50.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B
AU - Stofega, M R
AU - Herrington, J
AU - Billestrup, Nils
AU - Carter-Su, C
PY - 2000/9
Y1 - 2000/9
N2 - Binding of GH to GH receptor (GHR) rapidly and transiently activates multiple signal transduction pathways that contribute to the growth-promoting and metabolic effects of GH. While the events that initiate GH signal transduction, such as activation of the Janus tyrosine kinase JAK2, are beginning to be understood, the signaling events that terminate GH signaling, such as dephosphorylation of tyrosyl-phosphorylated signaling molecules, are poorly understood. In this report, we examine the role of the SH2 (Src homology-2) domain-containing protein tyrosine phosphatase SHP-2 in GH signaling. We demonstrate that the SH2 domains of SHP-2 bind directly to tyrosyl phosphorylated GHR from GH-treated cells. Tyrosine-to-phenylalanine mutation of tyrosine 595 of rat GHR greatly diminishes association of the SH2 domains of SHP-2 with GHR, and tyrosine-to-phenylalanine mutation of tyrosine 487 partially reduces association of the SH2 domains of SHP-2 with GHR. Mutation of tyrosine 595 dramatically prolongs the duration of tyrosyl phosphorylation of the signal transducer and activator of transcription STAT5B in response to GH, while mutation of tyrosine 487 moderately prolongs the duration of STAT5B tyrosyl phosphorylation. Consistent with the effects on STAT5B phosphorylation, tyrosine-to-phenylalanine mutation of tyrosine 595 prolongs the duration of tyrosyl phosphorylation of GHR and JAK2. These data suggest that tyrosine 595 is a major site of interaction of GHR with SHP-2, and that GHR-bound SHP-2 negatively regulates GHR/JAK2 and STAT5B signaling.
AB - Binding of GH to GH receptor (GHR) rapidly and transiently activates multiple signal transduction pathways that contribute to the growth-promoting and metabolic effects of GH. While the events that initiate GH signal transduction, such as activation of the Janus tyrosine kinase JAK2, are beginning to be understood, the signaling events that terminate GH signaling, such as dephosphorylation of tyrosyl-phosphorylated signaling molecules, are poorly understood. In this report, we examine the role of the SH2 (Src homology-2) domain-containing protein tyrosine phosphatase SHP-2 in GH signaling. We demonstrate that the SH2 domains of SHP-2 bind directly to tyrosyl phosphorylated GHR from GH-treated cells. Tyrosine-to-phenylalanine mutation of tyrosine 595 of rat GHR greatly diminishes association of the SH2 domains of SHP-2 with GHR, and tyrosine-to-phenylalanine mutation of tyrosine 487 partially reduces association of the SH2 domains of SHP-2 with GHR. Mutation of tyrosine 595 dramatically prolongs the duration of tyrosyl phosphorylation of the signal transducer and activator of transcription STAT5B in response to GH, while mutation of tyrosine 487 moderately prolongs the duration of STAT5B tyrosyl phosphorylation. Consistent with the effects on STAT5B phosphorylation, tyrosine-to-phenylalanine mutation of tyrosine 595 prolongs the duration of tyrosyl phosphorylation of GHR and JAK2. These data suggest that tyrosine 595 is a major site of interaction of GHR with SHP-2, and that GHR-bound SHP-2 negatively regulates GHR/JAK2 and STAT5B signaling.
KW - 3T3 Cells
KW - Amino Acid Substitution
KW - Animals
KW - Binding Sites
KW - DNA-Binding Proteins
KW - Human Growth Hormone
KW - Humans
KW - Janus Kinase 2
KW - Kinetics
KW - Mice
KW - Milk Proteins
KW - Mutagenesis, Site-Directed
KW - Phenylalanine
KW - Phosphotyrosine
KW - Protein-Tyrosine Kinases
KW - Proto-Oncogene Proteins
KW - Rats
KW - Receptors, Somatotropin
KW - Recombinant Proteins
KW - STAT5 Transcription Factor
KW - Signal Transduction
KW - Trans-Activators
KW - Tyrosine
KW - src Homology Domains
U2 - 10.1210/mend.14.9.0513
DO - 10.1210/mend.14.9.0513
M3 - Journal article
C2 - 10976913
VL - 14
SP - 1338
EP - 1350
JO - Molecular Endocrinology
JF - Molecular Endocrinology
SN - 0888-8809
IS - 9
ER -
ID: 132900095