A Novel C-Terminal Growth Hormone Receptor (GHR) Mutation Results in Impaired GHR-STAT5 But Normal STAT-3 Signaling

Tiulpakov, Anatoly; Rubtsov, P. M.; Дедов, И И; Peterkova, Valentina; Безлепкина, О. Б.; Chrousos, George P.; Hochberg, Zèev

doi:10.1210/jc.2003-2133

Cited by 45 publications

(21 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…(12)(13)(14)(15) In humans, mutations of GHR or that result in the inhibition of STAT-5b signaling without alteration of STAT-1 and -3, MAPK or ERK signaling results in severe IGF-1 deficiency and short stature. (16)(17)(18)(19) To date, the specific STAT family member(s) activated during GH signaling in growth plate chondrocytes has focused on STAT-5, and a role for STAT-1 and -3 is, as yet, unknown. (20) Furthermore, systemic therapy with recombinant human IGF-1 in children with IGF-1 deficiency improves but generally does not normalize growth.…”

mentioning

confidence: 99%

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

Pass

MacRae

Huesa

et al. 2012

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Suppressor of Cytokine Signaling-2 (SOCS2) is a negative regulator of growth hormone (GH) signaling and bone growth via inhibition of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. This has been classically demonstrated by the overgrowth phenotype of SOCS2 À/À mice, which has normal systemic insulin-like growth factor 1 (IGF-1) levels. The local effects of GH on bone growth are equivocal, and therefore this study aimed to understand better the SOCS2 signaling mechanisms mediating the local actions of GH on epiphyseal chondrocytes and bone growth. SOCS2, in contrast to SOCS1 and SOCS3 expression, was increased in cultured chondrocytes after GH challenge. Gain-and loss-of-function studies indicated that GH-stimulated chondrocyte STATs-1, -3, and -5 phosphorylation was increased in SOCS2 À/À chondrocytes but not in cells overexpressing SOCS2. This increased chondrocyte STAT signaling in the absence of SOCS2 is likely to explain the observed GH stimulation of longitudinal growth of cultured SOCS2À/À embryonic metatarsals and the proliferation of chondrocytes within. Consistent with this metatarsal data, bone growth rates, growth plate widths, and chondrocyte proliferation were all increased in SOCS2 À/À 6-week-old mice as was the number of phosphorylated STAT-5-positive hypertrophic chondrocytes. The SOCS2 À/À mouse represents a valid model for studying the local effects of GH on bone growth. ß

show abstract

mentioning

confidence: 99%

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

Pass

MacRae

Huesa

et al. 2012

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…This is further supported by a C-terminal GHR mutation recently identified in a patient with severe short stature and biochemical features of GH insensitivity. This GHR mutant results in impaired STAT5 but normal STAT3 signaling (58). Furthermore, JAK2 but not GHR, contains STAT3 association motifs and a STAT1-like association motif (59,60), suggesting that JAK2 not only phosphorylates STAT1 and STAT3 but also provides binding sites for their association with the GHR⅐JAK2 complex.…”

Section: Discussionmentioning

confidence: 98%

Insulin Reverses Growth Hormone-induced Homologous Desensitization

Liu

Clemens

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Growth hormone (GH) is secreted in a pulsatile pattern to promote body growth and metabolism. GH exerts its function by activating several signaling pathways, including JAK2/STAT and MEK/ERK. ERK1/2 activation by GH plays important roles in gene expression, cell proliferation, and growth. We previously reported that in rat H4IIE hepatoma cells after an initial GH exposure, a second GH exposure induces STAT5 phosphorylation but not ERK1/2 phosphorylation (Ji, S., Frank, S. J., and Messina, J. L. (2002) J. Biol. Chem. 277, 28384 -28393). In this study the mechanisms underlying GH-induced homologous desensitization were investigated. A second GH exposure activated the signaling intermediates upstream of MEK/ERK, including JAK2, Ras, and Raf-1. This correlated with recovery of GH receptor levels, but was insufficient for GH-induced phosphorylation of MEK1/2 and ERK1/2. Insulin restored the ability of a second GH exposure to induce phosphorylation of MEK1/2 and ERK1/2 without altering GH receptor levels or GH-induced phosphorylation/activation of JAK2 and Raf-1. GH and insulin synergized in promoting cell proliferation. Further investigation suggested that insulin increased the amount of MEK bound to KSR (kinase suppressor of Ras) and restored GH-induced tyrosine phosphorylation of KSR. Previous GH exposure also induced desensitization of STAT1 and STAT3 phosphorylation, but this desensitization was not reversed by insulin. Thus, insulin-regulated resensitization of GH signaling may be necessary to reset the complete response to GH after a normal, physiologic pulse of GH. Binding of GH to its receptor (GHR)2 results in tyrosine phosphorylation of Janus-activating kinase (JAK) 2 and GHR (1, 2), leading to the activation of signal transducer and activator of transcription (STAT) proteins (2-4). GH also activates ERK1/2 via the Ras/Raf-1/MEK/ERK cascade (5-8). An activated GHR⅐JAK2 complex recruits and phosphorylates Shc, bringing Grb2 and Son of Sevenless (SOS) to the cell membrane, resulting in the formation of active GTP-bound Ras. Ras activation initiates the activation of Raf-1 kinase, which leads to the phosphorylation and activation of MEK1/2 and then ERK1/2. Activation of ERK1/2 plays an important role in GH-induced gene expression, cell proliferation and growth, and cross-talk between GH and other growth factor signaling pathways (9 -13).GH is secreted in a pulsatile fashion (14, 15). In young adult male rats, GH is released in ϳ1-h pulses with peak serum concentrations of 150 -400 ng/ml and interpulse intervals of 2 h or more, where serum GH concentrations are negligible (16). In female rats, GH is secreted more frequently, resulting in the continuous presence of GH in the circulation, which peaks at 50 -150 ng/ml (15-18). After stimulation by a GH pulse, an obligatory recovery period is required for a succeeding GH pulse to induce STAT5 phosphorylation (19 -21). Reactivation of STAT5b by the masculine, but not the feminine, GH secretory pattern is important in transducing the sexually dimorphic pattern of GH ...

show abstract

“…Fourteen nonsense mutations in GHR were described (Table 2), being 2 of them located in exon 5 (22,23). …”

Section: Discussionmentioning

confidence: 99%

Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome

Diniz

Jorge

Arnhold

et al. 2008

Arq Bras Endocrinol Metab

View full text Add to dashboard Cite

Background: To date, about sixty different mutations within GH receptor (GHR) gene have been described in patients with GH insensitivity syndrome (GHI). In this report, we described a novel nonsense mutation of GHR. Methods: The patient was evaluated at the age of 6 yr, for short stature associated to clinical phenotype of GHI. GH, IGF-1, and GHBP levels were determined. The PCR products from exons 2-10 were sequenced. Results: The patient had high GH (26 µg/L), low IGF-1 (22.5 ng/ml) and undetectable GHBP levels. The sequencing of GHR exon 5 disclosed adenine duplication at nucleotide 338 of GHR coding sequence (c.338dupA) in homozygous state. Conclusion: We described a novel mutation that causes a truncated GHR and a loss of receptor function due to the lack of amino acids comprising the transmembrane and intracellular regions of GHR protein, leading to GHI.

show abstract

A Novel C-Terminal Growth Hormone Receptor (GHR) Mutation Results in Impaired GHR-STAT5 But Normal STAT-3 Signaling

Cited by 45 publications

References 42 publications

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

Insulin Reverses Growth Hormone-induced Homologous Desensitization

Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome

Contact Info

Product

Resources

About