Growth Hormone Signalling Mechanisms: Involvement of the Tyrosine Kinase JAK2

Argetsinger, Lawrence S.; Carter‐Su, Christin

doi:10.1159/000184823

Cited by 31 publications

(18 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in view of the limited time of exposure to GH in our glucose transport study (1 hr), a direct effect by GH seems more likely and would be congruent with recent evidence that GH addition induces rapid tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and mitogen-activated protein kinases (48). GH effects on glucose transport were recently shown to be due to direct recruitment of the transporters GLUT1 and GLUT4 to the plasma membrane (49).…”

Section: Discussionsupporting

confidence: 87%

“…Fertilized eggs, two-cell embryos, morulae, and blastocysts were collected [24,48,72, and 96 hr after administration of 10 international units of human chorionic gonadotropin (hCG)] from mated, superovulated Quackenbush mice. RNA obtained by using extraction with phenol͞ chloroform and precipitation with ethanol (13) was reverse transcribed by oligo(dT) priming and avian myeloblastosis virus reverse transcriptase (GIBCO͞BRL).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Functional growth hormone (GH) receptors and GH are expressed by preimplantation mouse embryos: A role for GH in early embryogenesis?

Pantaleon

Whiteside

Harvey

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

The results of this study challenge the widely held view that growth hormone (GH) acts only during the postnatal period. RNA phenotyping shows transcripts for the GH receptor and GH-binding protein in mouse preimplantation embryos of all stages from fertilized eggs (day 1) to blastocysts (day 4). An antibody specific to the cytoplasmic region of the GH receptor revealed receptor protein expression, first in two-cell embryos, the stage of activation of the embryonic genome (day 2), and in all subsequent stages. In cleavage-stage embryos this immunoreactivity was localized mainly to the nucleus, but clear evidence of membrane labeling was apparent in blastocysts. GH receptor immunoreactivity was also observed in cumulus cells associated with unfertilized oocytes but not in the unfertilized oocytes. The blastocyst receptor was demonstrated to be functional, exhibiting the classic bell-shaped dose-response curves for GH stimulation of both 3-O-methyl glucose transport and protein synthesis. Maximal stimulation of 40-50% was seen for both responses at less than 1 ng͞ml recombinant GH, suggesting a role for maternal GH. However mRNA transcripts for GH were also detected from the morula stage (day 3) by using reverse transcription-PCR, and GH immunoreactivity was seen in blastocysts. These observations raise the possibility of a paracrine͞autocrine GH loop regulating embryonic development in its earliest stages.Embryonic and fetal growth have long been considered to be independent of pituitary growth hormone (GH). However, this view is challenged by a growing body of evidence which demonstrates a role for GH in the development of the fetus. Newborn Laron dwarfs, lacking a functional GH receptor, are more than 2 SD shorter than normal (1). Exogenous GH has been shown to restore embryonic growth in rats after transplantation of parts of embryos into hypophysectomized hosts (2). A number of fetal tissues has been shown to respond to GH in vitro (3-6). GH receptor transcripts have been demonstrated in day 12 rat embryos and placentae (7), day 51 sheep embryos (8), and mouse placenta (9). Immunoreactive GH receptor was observed in the human fetus from the second trimester (10, 11). Recently GH receptor transcripts and immunoreactivity have been demonstrated in germ-line competent mouse embryonic stem cells, and GH receptor transcripts were also demonstrated in mouse blastocysts (12).Preimplantation stages earlier than the blastocyst, however, were not examined by Ohlsson et al. (12). Furthermore, there was no evidence that these very early embryos were capable of receptor synthesis or of signal transduction after ligand binding to expressed receptor. In this study we demonstrate the presence of GH receptors in the early embryo from fertilization to the blastocyst stage and the ability of GH to influence the metabolism of blastocyst. Moreover, we report the expression of GH by preimplantation blastocysts, raising the possibility of paracrine͞autocrine regulation of embryonic growth by GH. MATERIALS AND METHODSGene Ex...

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Functional growth hormone (GH) receptors and GH are expressed by preimplantation mouse embryos: A role for GH in early embryogenesis?

Pantaleon

Whiteside

Harvey

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

show abstract

“…GH is a member of the cytokine superfamily of receptors (58). A crucial step in its signaling process is the recruitment and activation of JAK-2, a tyrosyl protein kinase (2). The ability of GH to stimulate PDE4A5 is clearly dependent on such a protein as depletion of JAK-2 by an antisense strategy (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The receptor for this hormone interacts with the cytosolic tyrosyl kinase JAK-2 to initiate signaling cascades (2). These include the activation of the STAT family of transcription factors, PI 3-kinase and the ERK2 MAPK cascade (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

Stimulation of p70S6 kinase via a growth hormone-controlled phosphatidylinositol 3-kinase pathway leads to the activation of a PDE4A cyclic AMP-specific phosphodiesterase in 3T3-F442A preadipocytes

Mackenzie

Yarwood

Peden

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The challenge of 3T3-F442A fibroblasts with growth hormone led to both a decrease in the mobility on SDS͞PAGE and activation of the PDE4A cyclic AMP-specific phosphodiesterase isoform PDE4A5. Activation was mediated by a JAK-2-dependent pathway coupled to the activation of phosphatidylinositol 3-kinase and p70S6 kinase. Activation was not dependent on the ability of growth hormone to stimulate ERK2 or protein kinase C or any effect on transcription. Blockade of activation of murine PDE4A5 ablated the ability of growth hormone to decrease intracellular cAMP levels. Antisense depletion of murine PDE4A5 mimicked the ability of rolipram to enhance the growth hormone-stimulated differentiation of 3T3-F442A cells to adipocytes. It is suggested that activation of PDE4A5 by growth hormone serves as a brake on the differentiation processes.

show abstract

“…Shc is responsible for the activation of the mixed-function tyrosine/serine/threonine kinases MEKs (mitogen-activated protein kinases [MAPKs] that in turn activate the extracellular signalrelated kinanes [ERKs]) MAPKs, important for the mitogenic response (4). JAK is also the mediator of insulin-like effects of some polypeptides like growth hormone through phosphorylation of IRS and activation of their downstream effectors phosphatidylinositol (PI) 3-kinase and Akt, mainly required for metabolic functions (5)(6)(7)(8). Moreover, JAK is the cytoplasmic kinase through which circulating factors such as tumor necrosis factor-␣ and pro-inflammatory cytokines negatively regulate insulin action through serine phosphorylation of IRS-1 or induction of suppressors of cytokine signaling (SOCS) expression (9).…”

mentioning

confidence: 99%

Opposite Effect of JAK2 on Insulin-Dependent Activation of Mitogen-Activated Protein Kinases and Akt in Muscle Cells

et al. 2006

View full text Add to dashboard Cite

Many cytokines increase their receptor affinity for Janus kinases (JAKs). Activated JAK binds to signal transducers and activators of transcription, insulin receptor substrates (IRSs), and Shc. Intriguingly, insulin acting through its own receptor kinase also activates JAK2. However, the impact of such activation on insulin action remains unknown. To determine the contribution of JAK2 to insulin signaling, we transfected L6 myotubes with siRNA against JAK2 (siJAK2), reducing JAK2 protein expression by 75%. Insulin-dependent phosphorylation of IRS1/2 and Shc was not affected by siJAK2, but insulin-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-related kinase, p38, and Jun NH 2 -terminal kinase and their respective upstream kinases MKK1/2, MKK3/6, and MKK4/7 was significantly lowered when JAK2 was depleted, correlating with a significant drop in insulin-mediated cell proliferation. These effects were reproduced by the JAK2 inhibitor AG490. Conversely, insulin-stimulated Akt phosphorylation, glucose uptake, and GLUT4 translocation were not affected by siJAK2. Interestingly, in two insulin-resistant states, siJAK2 led to partial restoration of Akt phosphorylation and glucose uptake stimulation but not of the MAPK pathway. These results suggest that JAK2 may depress the Akt to glucose uptake signaling axis selectively in insulin-resistant states. Inhibition of JAK2 may be a useful strategy to relieve insulin resistance of metabolic outcomes. Diabetes 55: 942-951, 2006 P olypeptides such as erythropoietin, prolactin, leptin, angiotensin, growth hormone, most interleukins, and interferon-␥ bind to receptors that lack intrinsic kinase activity, recruiting and activating cytoplasmic tyrosine kinases of the Janus family (JAK) consisting of JAK1, JAK2, JAK3, and Tyk2 (1-3). Activated JAK phosphorylates tyrosine residues within itself and the associated receptor forming high-affinity binding sites for a variety of signaling proteins containing Src homology 2 and other phosphotyrosine-binding domains, including signal transducers and activators of transcription, insulin receptor substrates (IRSs), and the adaptor protein Shc (1-4). Shc is responsible for the activation of the mixed-function tyrosine/serine/threonine kinases MEKs (mitogen-activated protein kinases [MAPKs] that in turn activate the extracellular signalrelated kinanes [ERKs]) MAPKs, important for the mitogenic response (4). JAK is also the mediator of insulin-like effects of some polypeptides like growth hormone through phosphorylation of IRS and activation of their downstream effectors phosphatidylinositol (PI) 3-kinase and Akt, mainly required for metabolic functions (5-8). Moreover, JAK is the cytoplasmic kinase through which circulating factors such as tumor necrosis factor-␣ and pro-inflammatory cytokines negatively regulate insulin action through serine phosphorylation of IRS-1 or induction of suppressors of cytokine signaling (SOCS) expression (9).Insulin increases the autophosphorylation and tyrosine kinas...

show abstract

Growth Hormone Signalling Mechanisms: Involvement of the Tyrosine Kinase JAK2

Cited by 31 publications

References 13 publications

Functional growth hormone (GH) receptors and GH are expressed by preimplantation mouse embryos: A role for GH in early embryogenesis?

Functional growth hormone (GH) receptors and GH are expressed by preimplantation mouse embryos: A role for GH in early embryogenesis?

Stimulation of p70S6 kinase via a growth hormone-controlled phosphatidylinositol 3-kinase pathway leads to the activation of a PDE4A cyclic AMP-specific phosphodiesterase in 3T3-F442A preadipocytes

Opposite Effect of JAK2 on Insulin-Dependent Activation of Mitogen-Activated Protein Kinases and Akt in Muscle Cells

Contact Info

Product

Resources

About