Distinct cytoplasmic regions of the growth hormone receptor are required for activation of JAK2, mitogen-activated protein kinase, and transcription.

Sotiropoulos, Athanassia; Perrot‐Applanat, Martine; Dinerstein, H.; Pallier, Annaïck; Postel-Vinay, Marie-Catherine; Finidori, J.; Kelly, Paul A.

doi:10.1210/endo.135.4.7925092

Cited by 104 publications

(74 citation statements)

References 16 publications

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“…Perhaps we can look for guidance to recent examples of the structures and functions of members of the cytokineÏgrowth hormoneÏprolactin receptor superfamily, where a single gene in this family can give rise to multiple membrane, cytoplasmic, and transcriptional activities (Sotiropoulos et al 1994;Ferrag et al 1997). Consequences for the functioning of many different tissues are implied, although only the pituitary, pancreatic and cardiovascular systems were specifically cited here.…”

Section: Discussionmentioning

confidence: 99%

Membrane Oestrogen Receptors on Rat Pituitary Tumour Cells: Immuno‐Identification and Responses to Oestradiol and Xenoestrogens

Watson

Campbell

Gametchu

1999

Experimental Physiology

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summaryOur laboratory has identified plasma membrane oestrogen receptors on a GH×ÏB6 rat pituitary tumour cell line and several sublines which produce rapid (within minutes), non-genomic responses to oestrogens. Oestrogen receptors have been identified by their binding to nine different antibodies (Abs) which together recognize at least seven epitopes on the oestrogen receptor-á. GH×ÏB6ÏF10 cells, a membrane oestrogen receptor-enriched subline, elevate intracellular calcium levels in response to 10 nÒ oestradiol. Prolactin release in these cells is triggered by both 1 pÒ and 1 nÒ oestradiol and diethylstilbestrol (DES). A membrane oestrogen receptor-á immunocyto-chemical signal rapidly disappears (at 3 min) and reappears (at 12-15 min) when 1 nÒ oestradiol,

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Section: Discussionmentioning

confidence: 99%

Membrane Oestrogen Receptors on Rat Pituitary Tumour Cells: Immuno‐Identification and Responses to Oestradiol and Xenoestrogens

Watson

Campbell

Gametchu

1999

Experimental Physiology

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“…In contrast to STAT5 activation, which requires the presence of the receptor cytoplasmic domain in addition to activation of JAK2, the ability of GH to activate ERKs appears to require none of the distal GHR tail and instead corresponds to whether it can promote JAK2 activation (9,(11)(12)(13). However, ERK is not activated in all cells in which GH activates JAK2 (14).…”

Section: Growth Hormone (Gh)mentioning

confidence: 99%

Growth Hormone-induced Phosphorylation of Epidermal Growth Factor (EGF) Receptor in 3T3-F442A Cells

Huang

Kim

Jiang

et al. 2003

Journal of Biological Chemistry

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Growth hormone (GH) promotes signaling by causing activation of the non-receptor tyrosine kinase, JAK2, which associates with the GH receptor. GH causes phosphorylation of epidermal growth factor receptor (EGFR; ErbB-1) and its family member, ErbB-2. For EGFR, JAK2-mediated GH-induced tyrosine phosphorylation may allow EGFR to serve as a scaffold for GH signaling. For ErbB-2, GH induces serine/threonine phosphorylation that dampens basal and EGF-induced ErbB-2 kinase activation. We now further explore GH-induced EGFR phosphorylation in 3T3-F442A, a preadipocytic fibroblast cell line that expresses endogenous GH receptor, EGFR, and ErbB-2. Using a monoclonal antibody that recognizes ERK consensus site phosphorylation (PTP101), we found that GH caused PTP101-reactive phosphorylation of EGFR. This GH-induced EGFR phosphorylation was prevented by MEK1 inhibitors but not by a protein kinase C inhibitor. Although GH did not discernibly affect EGF-induced EGFR tyrosine phosphorylation, we observed by immunoblotting a substantial decrease of EGF-induced EGFR degradation in the presence of GH. Fluorescence microscopy studies indicated that EGF-induced intracellular redistribution of an EGFR-cyan fluorescent protein chimera was markedly reduced by GH cotreatment, in support of the immunoblotting results. Notably, protection from EGF-induced degradation and inhibition of EGF-induced intracellular redistribution afforded by GH were both prevented by a MEK1 inhibitor, suggesting a role for GH-induced ERK activation in regulating the trafficking itinerary of the EGF-stimulated EGFR. Finally, we observed augmentation of early aspects of EGF signaling (EGF-induced ERK2 activation and EGF-induced Cbl tyrosine phosphorylation) by GH cotreatment; the GH effect on EGF-induced Cbl tyrosine phosphorylation was also prevented by MEK1 inhibition. These data indicate that GH, by activating ERKs, can modulate EGF-induced EGFR trafficking and signaling and expand our understanding of mechanisms of cross-talk between the GH and EGF signaling systems.

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“…To elucidate the domains in the GH receptor required for activation of Stat(s) and Jak2, cell lines containing deletions in the cytoplasmic domain of the human receptor have been analyzed for GH-stimulated tyrosine phosphorylation of Jak2 and GRR binding activity. These studies demonstrated the importance of box 1 and box 2 in GH activation of Jak2 kinase and the Stat transcription factors (5,(7)(8)(9)(10)(11). However, little if any information has been reported concerning the role of other domains within the cytoplasmic region of the receptor in the modulation of GH activation of the Jak/Stat pathway.…”

Section: Growth Hormone (Gh)mentioning

confidence: 99%

Mapping of a Cytoplasmic Domain of the Human Growth Hormone Receptor That Regulates Rates of Inactivation of Jak2 and Stat Proteins

Hackett

Wang²,

Sweitzer

et al. 1997

Journal of Biological Chemistry

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It has been previously demonstrated that growth hormone (GH)-stimulated tyrosine phosphorylation of Jak2 and Stat5a and Stat5b occurs in FDP-C1 cells expressing either the entire GH receptor or truncations of the cytoplasmic domain expressing only the membrane-proximal 80 amino acids. However, other receptor domains that might modulate rates of GH activation and inactivation of this cascade have not been examined. Here we have defined a region in the human GH receptor between amino acids 520 and 540 in the cytoplasmic domain that is required for attenuation of GH-activated Jak/Stat signaling. Immunoprecipitations with antibodies to Jak2 indicate that the protein tyrosine phosphatase SHP-1 is associated with this kinase in cells exposed to GH. To address the possibility that SHP-1 could function as a negative regulator of GH signaling, liver extracts from motheaten mice deficient in SHP-1 or unaffected littermates were analyzed for activation of Stats and Jak2. Extracts from motheaten mice displayed prolonged activation of the Stat proteins as measured by their ability to interact with DNA and prolonged tyrosine phosphorylation of Jak2. These results delineate a novel domain in the GH receptor that regulates the inactivation of the Jak/Stat pathway and appears to be modulated by SHP-1. Growth hormone (GH)1 exerts its pleiotropic actions on a variety of tissues including fat, bone, soft tissue, and liver. One of the earliest events that occurs after GH binds to its cell surface receptor is the tyrosine phosphorylation of several cellular proteins, including the SH2 domain-containing transcription factors termed signal transducers and activators of transcription or Stats (1-4). Tyrosine phosphorylated Stat proteins bind enhancers that are present in genes whose transcription is rapidly induced by the treatment of cells with GH and other cytokines. One of these enhancers is the gamma response region (GRR) present in the promoter of the Fc␥RI receptor gene. This enhancer, which is required for IFN␥-activated transcription of the Fc␥RI receptor gene, has a sequence similar to those of enhancers that are required for the activation of cellular genes by a variety of other cytokines. GRR binding activity can be measured in many cells in response to growth hormone treatment, and it serves as an assay for the tyrosine phosphorylation of Stat proteins (1, 5). Most of the cytokine receptors interact with members of the Jak family of tyrosine kinases, and Jak activation closely parallels and in many cases is required for Stat protein phosphorylation on tyrosine. Tyrosine phosphorylated Jak2 has been shown to associate with the GHR after the addition of ligand, which allows Stat1, Stat3, Stat5a, and Stat5b to also be phosphorylated (6).The receptors for growth hormone and other members of this cytokine receptor superfamily have several conserved features including cysteine residues within their extracellular domains and two intracellular subdomains (termed box 1 and box 2) adjacent to the transmembrane region. To elucidate the...

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Distinct cytoplasmic regions of the growth hormone receptor are required for activation of JAK2, mitogen-activated protein kinase, and transcription.

Cited by 104 publications

References 16 publications

Membrane Oestrogen Receptors on Rat Pituitary Tumour Cells: Immuno‐Identification and Responses to Oestradiol and Xenoestrogens

Membrane Oestrogen Receptors on Rat Pituitary Tumour Cells: Immuno‐Identification and Responses to Oestradiol and Xenoestrogens

Growth Hormone-induced Phosphorylation of Epidermal Growth Factor (EGF) Receptor in 3T3-F442A Cells

Mapping of a Cytoplasmic Domain of the Human Growth Hormone Receptor That Regulates Rates of Inactivation of Jak2 and Stat Proteins

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