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Molecular Events in Growth Hormone–Receptor Interaction and Signaling

Lisa S. Smit, Debra J. Meyer, Lawrence S. Argetsinger, Jessica Schwartz, Christin Carter‐Su

10.1002/cphy.cp070514

Source: Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth

Originally published: 1999

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 The Growth Hormone Receptor
1.1 Cloning of the Growth Hormone Receptor
1.2 The Cytokine/Hematopoietin Receptor Superfamily
1.3 Growth Hormone Binding and Receptor Dimerization
2 Growth Hormone–Dependent Intracellular Signaling
2.1 Activation of the Tyrosine Kinase Janus Kinase 2
2.2 Tyrosyl Phosphorylation of the Growth Hormone Receptor and Janus Kinase 2
2.3 Activation of the Ras–Mitogen‐Activated Protein Kinase Signaling Pathway
2.4 Utilization of Insulin Receptor Substrates 7 and 2 and Phosphatidylinositol‐3′‐Kinase
2.5 Regulation of Protein Kinase C
2.6 Regulation of Intracellular Calcium
2.7 Activation of Stat Proteins
3 Growth Hormone‐Dependent Signaling to the Nucleus
3.1 Multiple Pathways Mediate Growth Hormone–Regulated Gene Expression
3.2 Sexually Dimorphic Growth Hormone Secretion Patterns Regulate Gene Transcription
4 Conclusions
Figure 1. Figure 1.

Members of the cytokine receptor superfamily are schematically illustrated, including the specific receptors (R) for growth hormone (GH); prolactin (PRL); erythropoietin (EPO); granulocyte colony‐stimulating factor (G‐CSF); ciliary neurotrophic factor (CNTP); leukemia‐inhibitory factor (LIF); oncostatin M (OSM); leptin (Ob‐Rb); thrombopoietin (mpl); granulocyte‐macrophage colony‐stimulating factor (GM‐CSF); interleukins (IL) 2–7, 9–13, and 15; and interferon (IFN)‐γ and‐α as well as shared receptor subunits including the IL‐3 receptor common β chain (Aic‐2/βc), the IL‐2 receptor common γ chain (γc), and gp 130. Conserved extracellular cysteine motifs are represented by four thin lines. Extracellular WSXWS motifs are represented by black boxes (a thinner box represents WSXWS‐like motifs with conservative substitutions). Numbered white boxes in the intracellular region represent the conserved Box 1 and Box 2 regions. Dotted lines indicate putative receptor complexes employed by ligand.

From 9, with permission
Figure 2. Figure 2.

Growth hormone (GH) increases tyrosyl phosphorylation of multiple cellular proteins in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were treated with or without 23 nM (500 ng/ml) GH for the indicated times at 37°C. Whole‐cell lysates were prepared, fractionated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and transferred to nitrocellulose membranes. The resulting blot was probed with antiphosphotyrosine antibody. Eleven novel tyrosyl‐phosphorylated bands are observed in response to GH, indicating that GH induces tyrosyl phosphorylation of multiple proteins.

From 33, with permission
Figure 3. Figure 3.

Growth hormone (GH) induces Janus kinase (JAK2) activity and tyrosyl phosphorylation. A: Cells, 3T3–F442A, were incubated at 25°C in the absence (lane A) or presence (lanes B–D) of 30 ng/ml human GH for 1 h. Solubilized proteins were immunoprecipitated using anti‐JAK2 antibody, incubated with [γ – 32P] ATP, and subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis and autoradiography (lanes A and B). The presence of a dark band in lane B, but not in lane A, indicates that GH activates JAK2, as assessed by JAK2 autophosphorylation. Then, JAK2 was excised from the gel (lane B) and subjected to limited acid hydrolysis at 109°C for 1.25 h. Following partial purification on Dowex‐50, fractions containing O‐phosphoserine and O‐phosphothreonine (lane C) or O‐phosphotyrosine (lane D) were resolved by thin‐layer electrophoresis (pH 3.5). Migrations of O‐phosphoserine (P‐Ser), O‐phosphothreonine (P‐Thr), and O‐phosphotyrosine (P‐Tyr) standards are indicated by the dashed circles. Greater than 99% of the 32P incorporated into JAK2 in the in vitro kinase assay co‐migrated with O‐phosphotyrosine, indicating that JAK2 is a tyrosine kinase. B: Fibroblasts, 3T3–F442A, were incubated with the indicated concentrations of human GH for the times shown. Whole‐cell lysates were immunoprecipitated with antibody to JAK2. Immunoprecipitated proteins were subjected to Western blot analysis using antiphosphotyrosine antibody. The GH‐dependent signal indicates that in intact cells JAK2 is tyrosyl‐phosphorylated in response to GH.

Part A from 8, with permission; part B from 36, with permission
Figure 4. Figure 4.

Growth hormone (GH) receptor. Potential N‐linked glycosylation sites (N) and the extracellular cysteines (C) with three pairs of linked disulfide bonds are noted. The transmembrane domain is shown in black. The ten tyrosines (Y) present in the cytoplasmic region of rat GH receptor are noted. The position of the WSXWS‐like motif is indicated by the striped box. Intracellular Box 1 (proline‐rich domain) and Box 2 are shown as gray boxes. Regions of the receptor required for various functions are indicated. MAP, mitogen‐activated protein; JAK, Janus kinase; IRS, insulin receptor substrate.

From 9, with permission
Figure 5. Figure 5.

Possible signaling pathways initiated by binding of growth hormone (GH) to its receptor are shown. Solid arrows indicate pathways regulated by GH. Dotted arrows indicate pathways utilized by other growth factors but not yet shown to be involved in GH‐dependent signal transduction or pathways with only limited data to support their existence. P, phosphorylated tyrosines; JAK, Janus kinase; IRS, insulin receptor substrate; PI3K, phosphatidylinositol‐3‐kinase; PC‐PLC, phosphocholine–phospholipase C; DAG, diacylglycerol; PKC, protein kinsase C; SOS, son of sevenless; MAPK, mitogen‐activated protein kinase; MEK, MAPK/ERK kinase; PLA2; phospholipase A2; SRF, serum response factor; TCF, ternary complex factor; SIE, Sis‐inducible element; SRE, serum response elements; AP1, activator protein‐1; GLE, interferon‐γ‐activated sequence–like element.

From 9, with permission
Figure 6. Figure 6.

Growth hormone (GH) activates extracellular signal–regulated kinases (ERKs) 1 and 2. Fibroblasts, 3T3–F442A, were incubated with 23 nM (500 ng/ml) human GH for the times indicated. Whole‐cell lysates were blotted with an antibody which detects only the active, doubly phosphorylated form of ERKs 1 and 2. The GH‐dependent signal observable by 5 min indicates that GH induces phosphorylation and activation of ERKs 1 and 2.
Figure 7. Figure 7.

Growth hormone receptor (GHR) signaling via the extracellular signal–regulated kinases (ERKs) 1 and 2. A signaling cascade leading from GHR to the mitogen‐activated protein (MAP) kinase and activation of subsequent targets is shown. Solid arrows and signaling molecules and bold targets indicate pathways and proteins regulated by GH. Dotted arrows and targets in medium type indicate pathways, feedback mechanisms, and targets utilized in cells treated with other cytokines and growth factors that activate MAP kinase or are detected in vitro. These have not yet been shown to be involved in GH signal transduction. PLC, phospholipase C; PLA2, phospholipase A2; TCF, ternary complex factor; JAK, Janus kinase; GTP, guanosine triphosphate; Sos, son of sevenless; MEK, MAP kinase/ERK kinase. TAL, T‐cell acute lymphoblastic leukemia gene; NF, nuclear factor IL‐6; ATF, activating transcription factor‐2; MAPKAP, MAP kinase activated protein kinase‐2.
Figure 8. Figure 8.

Growth hormone (GH) promotes tyrosyl phosphorylation of insulin receptor substrate‐1 (IRS‐1). Fibroblasts, 3T3–F442A, were incubated at 37°C with 23 nM (500 ng/ml) human GH or 170 ng/ml insulin‐like growth factor I (IGF‐1) for the times indicated. Whole‐cell lysates were immunoprecipitated with antibodies to IRS‐1 (αIRS‐1), GH (αGH), or Janus kinase (αJAK2). The lane on the far right was loaded with one‐tenth of the volume of sample loaded in the other lanes. Immunoprecipitated proteins were immunoblotted (Blot) with antiphosphotyrosine antibody (αPY). Molecular weights (x 10−3) of protein standards are indicated. Tyrosyl phosphorylation of IRS‐1 increases rapidly and transiently in response GH (first six lanes), and IRS‐1 coprecipitates with a tyrosyl‐phosphorylated complex that comigrates with GH receptors and JAK2 (first four lanes) and vice versa (last four lanes), suggesting that it forms a complex with GH receptor and JAK2 in a GH‐dependent manner.

From 36, with permission
Figure 9. Figure 9.

Growth hormone receptor (GHR) signaling via insulin receptor substrate‐1 (IRS‐1) and IRS‐2. Solid molecules and arrows indicate signaling molecules and pathways regulated by GH. Dashed molecules and arrows indicate signaling proteins known to bind IRS‐1 and/or IRS‐2 via SH2 domain–mediated interactions (Nck, Grb‐2, fyn) in response to insulin, proteins with enzymatic activities that are stimulated by the action of phosphatidylinositol‐3′‐kinase (PI3K), or signaling pathways utilized in cells treated with insulin. These have not yet been shown to be involved in GH signal transduction. SHP2, SH2 domain containing tyrosine phosphatase; JAK, Janus kinase.

From 9, with permission
Figure 10. Figure 10.

Growth hormone (GH) stimulates a rapid, transient increase in diacylglycerol (DAG) in Ob1771 cells. Postconfluent Ob1771 cells maintained in standard medium were exposed to 5 nM GH (open squares) or 200 nM prostaglandin F2a (solid squares) for various times. Formation of DAG was measured. The basal value obtained in the absence of GH (3.5 nmol/1000 nmol of phospholipid) was subtracted from the reported values. Each value represents the mean of pooled triplicate wells (differences between determinations were < 20%). These results indicate that GH elicits a rapid, transient increase in DAG in Ob1771 cells.

From 69, with permission
Figure 11. Figure 11.

Growth hormone (GH) induces an increase in cytosolic Ca2+([Ca2+])i) in single INS‐1 cells. Changes in ([Ca2+]i were investigated in fura‐2‐loaded cells stimulated with 5 nM bovine GH (bGH) at 3 mM glucose in the absence (A) or presence (B) of 1 mM calciseptine. Cells were attached on glass coverslips and loaded with 1 mM fura‐2 acetoxymethyl ester for 30 min. [Ca2+]i was monitored by the measurement of 340:380 nm ratio during continuous perfusion with Krebs‐Ringer bicarbonate HEPES buffer containing 3 mM glucose as a basal condition. Stimuli were given through large‐orifice pipettes placed in the vicinity of the cell examined. Representative traces of those obtained in at least five cells are shown. These results demonstrate that GH induces a transient rise in intracellular Ca2+ levels in INS‐1 cells. The observation that the GH‐induced increase in [Ca2+]i is blocked by calciseptine suggests that, in these cells, GH activates voltage‐dependent, L‐type calcium channels.

From 264, with permission
Figure 12. Figure 12.

Growth hormone (GH), leukemia‐inhibitory factor (LIF), and interferon‐γ (IFNγ) induce tyrosyl phosphorylation of Stat1, Stat3, and Stat5 in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were incubated in the absence of hormone or with 23 nM (500 ng/ml) human GH, 25 ng/ml human LIF, or 10 ng/ml murine IFNγ, as indicated, for 15 min. Whole‐cell lysates were immunoprecipitated with antibodies to Stat1 (αStat1), Stat3 (αStat3), or Stat5 (αStat5), as indicated. Immunoprecipitated proteins were subjected to Western blot analysis using antiphosphotyrosine antibody. Migrations of Stat1, Stat3, and Stat5 are indicated. Signals observed in response to GH indicate that GH stimulates tyrosyl phosphorylation of Stats 1, 3, and 5. The differences in relative signal intensities for GH, LIF, and IFNγ for each Stat suggest that the requirements for activation differ for each Stat protein.

From 36, with permission
Figure 13. Figure 13.

Growth hormone (GH) promotes tyrosyl phosphorylation of Stat5A and Stat5B in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were incubated without hormone (‐) or with 23 nM (500 ng/ml) human GH (+) for 15 min. Stat5 proteins were immunoprecipitated with antibodies to Stat5A (αStat5A) or Stat5B (αStat5B). Immunoprecipitates (IP) were subjected to Western blot analysis using antiphosphotyrosine antibody (αPY), αStat5A, or αStat5B. Tyrosyl phosphorylation of both Stat5A and 5B was induced by GH, as evidenced by the increased signal observed in lanes B and D compared to lanes A and C. Multiple Stat bands exist even in the absence of GH (lane E), suggesting the presence of multiple serine or threonine phosphorylation states.

From 281, with permission
Figure 14. Figure 14.

Growth hormone (GH)–induced Sis‐inducible element (SIE)–binding complex contains Stat1 and Stat3. An electrophoretic mobility shift assay was performed using the human SIE probe and nuclear extracts prepared from 3T3–F442A cells stimulated for 30 min with vehicle (control, lane 1), GH (500 ng/ml, lanes 2–4), leukemia‐inhibitory factor (LIF; 65 ng/ml, lanes 5–7), or interferon‐γ (IFNγ, 10 ng/ml, lanes 8–10). Nuclear extracts were preincubated for 20 min at room temperature with antibodies to Stat1 (αStat1; lanes 3, 6, and 9) or Stat3 (αStat3; lanes 5, 7, and 10). Nuclear extracts were then incubated with the radiolabeled DNA probe and subjected to electrophoresis. The detection of three bands in lane 2 (bands A, B, and C) and the observation that these bands can be supershifted with antibodies to Stats 1 and 3 indicate that GH induces binding of Stat1‐and Stat3‐containing complexes to the SIE.

From 34, with permission
Figure 15. Figure 15.

Serum response element (SRE) mediates induction of c‐fos by growth hormone (GH). Cells (NIH‐3T3) were transiently transfected with fos promoter plasmids and the α‐globin expression plasmid to indicate transfection efficiency. At 64 h after transfection, quiescent cells were stimulated with GH (500 ng/ml), 10% calf serum (CS), or vehicle (C, control) for 30 min. Total RNA was analyzed by ribonuclease protection assay. Positions of the protected fragments representing the human c‐fos reporter (upper arrow), α‐globin (middle arrow), and endogenous mouse c‐fos (lower arrow) transcripts are indicated. Hela cell RNA (H) provides a reference for the human c‐fos transcripts. A: Stimulation by GH of SRE‐FOS containing a single copy of the c‐fos SRE upstream of a human c‐fos reporter (from 222 bp upstream of the transcription start site through the coding region). B: Lack of induction of the reporter alone. C: Lack of induction of a mutant SRE‐FOS containing the reporter under control of a mutated SRE, which fails to bind serum response factor.

From 85, with permission


Figure 1.

Members of the cytokine receptor superfamily are schematically illustrated, including the specific receptors (R) for growth hormone (GH); prolactin (PRL); erythropoietin (EPO); granulocyte colony‐stimulating factor (G‐CSF); ciliary neurotrophic factor (CNTP); leukemia‐inhibitory factor (LIF); oncostatin M (OSM); leptin (Ob‐Rb); thrombopoietin (mpl); granulocyte‐macrophage colony‐stimulating factor (GM‐CSF); interleukins (IL) 2–7, 9–13, and 15; and interferon (IFN)‐γ and‐α as well as shared receptor subunits including the IL‐3 receptor common β chain (Aic‐2/βc), the IL‐2 receptor common γ chain (γc), and gp 130. Conserved extracellular cysteine motifs are represented by four thin lines. Extracellular WSXWS motifs are represented by black boxes (a thinner box represents WSXWS‐like motifs with conservative substitutions). Numbered white boxes in the intracellular region represent the conserved Box 1 and Box 2 regions. Dotted lines indicate putative receptor complexes employed by ligand.

From 9, with permission


Figure 2.

Growth hormone (GH) increases tyrosyl phosphorylation of multiple cellular proteins in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were treated with or without 23 nM (500 ng/ml) GH for the indicated times at 37°C. Whole‐cell lysates were prepared, fractionated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and transferred to nitrocellulose membranes. The resulting blot was probed with antiphosphotyrosine antibody. Eleven novel tyrosyl‐phosphorylated bands are observed in response to GH, indicating that GH induces tyrosyl phosphorylation of multiple proteins.

From 33, with permission


Figure 3.

Growth hormone (GH) induces Janus kinase (JAK2) activity and tyrosyl phosphorylation. A: Cells, 3T3–F442A, were incubated at 25°C in the absence (lane A) or presence (lanes B–D) of 30 ng/ml human GH for 1 h. Solubilized proteins were immunoprecipitated using anti‐JAK2 antibody, incubated with [γ – 32P] ATP, and subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis and autoradiography (lanes A and B). The presence of a dark band in lane B, but not in lane A, indicates that GH activates JAK2, as assessed by JAK2 autophosphorylation. Then, JAK2 was excised from the gel (lane B) and subjected to limited acid hydrolysis at 109°C for 1.25 h. Following partial purification on Dowex‐50, fractions containing O‐phosphoserine and O‐phosphothreonine (lane C) or O‐phosphotyrosine (lane D) were resolved by thin‐layer electrophoresis (pH 3.5). Migrations of O‐phosphoserine (P‐Ser), O‐phosphothreonine (P‐Thr), and O‐phosphotyrosine (P‐Tyr) standards are indicated by the dashed circles. Greater than 99% of the 32P incorporated into JAK2 in the in vitro kinase assay co‐migrated with O‐phosphotyrosine, indicating that JAK2 is a tyrosine kinase. B: Fibroblasts, 3T3–F442A, were incubated with the indicated concentrations of human GH for the times shown. Whole‐cell lysates were immunoprecipitated with antibody to JAK2. Immunoprecipitated proteins were subjected to Western blot analysis using antiphosphotyrosine antibody. The GH‐dependent signal indicates that in intact cells JAK2 is tyrosyl‐phosphorylated in response to GH.

Part A from 8, with permission; part B from 36, with permission


Figure 4.

Growth hormone (GH) receptor. Potential N‐linked glycosylation sites (N) and the extracellular cysteines (C) with three pairs of linked disulfide bonds are noted. The transmembrane domain is shown in black. The ten tyrosines (Y) present in the cytoplasmic region of rat GH receptor are noted. The position of the WSXWS‐like motif is indicated by the striped box. Intracellular Box 1 (proline‐rich domain) and Box 2 are shown as gray boxes. Regions of the receptor required for various functions are indicated. MAP, mitogen‐activated protein; JAK, Janus kinase; IRS, insulin receptor substrate.

From 9, with permission


Figure 5.

Possible signaling pathways initiated by binding of growth hormone (GH) to its receptor are shown. Solid arrows indicate pathways regulated by GH. Dotted arrows indicate pathways utilized by other growth factors but not yet shown to be involved in GH‐dependent signal transduction or pathways with only limited data to support their existence. P, phosphorylated tyrosines; JAK, Janus kinase; IRS, insulin receptor substrate; PI3K, phosphatidylinositol‐3‐kinase; PC‐PLC, phosphocholine–phospholipase C; DAG, diacylglycerol; PKC, protein kinsase C; SOS, son of sevenless; MAPK, mitogen‐activated protein kinase; MEK, MAPK/ERK kinase; PLA2; phospholipase A2; SRF, serum response factor; TCF, ternary complex factor; SIE, Sis‐inducible element; SRE, serum response elements; AP1, activator protein‐1; GLE, interferon‐γ‐activated sequence–like element.

From 9, with permission


Figure 6.

Growth hormone (GH) activates extracellular signal–regulated kinases (ERKs) 1 and 2. Fibroblasts, 3T3–F442A, were incubated with 23 nM (500 ng/ml) human GH for the times indicated. Whole‐cell lysates were blotted with an antibody which detects only the active, doubly phosphorylated form of ERKs 1 and 2. The GH‐dependent signal observable by 5 min indicates that GH induces phosphorylation and activation of ERKs 1 and 2.



Figure 7.

Growth hormone receptor (GHR) signaling via the extracellular signal–regulated kinases (ERKs) 1 and 2. A signaling cascade leading from GHR to the mitogen‐activated protein (MAP) kinase and activation of subsequent targets is shown. Solid arrows and signaling molecules and bold targets indicate pathways and proteins regulated by GH. Dotted arrows and targets in medium type indicate pathways, feedback mechanisms, and targets utilized in cells treated with other cytokines and growth factors that activate MAP kinase or are detected in vitro. These have not yet been shown to be involved in GH signal transduction. PLC, phospholipase C; PLA2, phospholipase A2; TCF, ternary complex factor; JAK, Janus kinase; GTP, guanosine triphosphate; Sos, son of sevenless; MEK, MAP kinase/ERK kinase. TAL, T‐cell acute lymphoblastic leukemia gene; NF, nuclear factor IL‐6; ATF, activating transcription factor‐2; MAPKAP, MAP kinase activated protein kinase‐2.



Figure 8.

Growth hormone (GH) promotes tyrosyl phosphorylation of insulin receptor substrate‐1 (IRS‐1). Fibroblasts, 3T3–F442A, were incubated at 37°C with 23 nM (500 ng/ml) human GH or 170 ng/ml insulin‐like growth factor I (IGF‐1) for the times indicated. Whole‐cell lysates were immunoprecipitated with antibodies to IRS‐1 (αIRS‐1), GH (αGH), or Janus kinase (αJAK2). The lane on the far right was loaded with one‐tenth of the volume of sample loaded in the other lanes. Immunoprecipitated proteins were immunoblotted (Blot) with antiphosphotyrosine antibody (αPY). Molecular weights (x 10−3) of protein standards are indicated. Tyrosyl phosphorylation of IRS‐1 increases rapidly and transiently in response GH (first six lanes), and IRS‐1 coprecipitates with a tyrosyl‐phosphorylated complex that comigrates with GH receptors and JAK2 (first four lanes) and vice versa (last four lanes), suggesting that it forms a complex with GH receptor and JAK2 in a GH‐dependent manner.

From 36, with permission


Figure 9.

Growth hormone receptor (GHR) signaling via insulin receptor substrate‐1 (IRS‐1) and IRS‐2. Solid molecules and arrows indicate signaling molecules and pathways regulated by GH. Dashed molecules and arrows indicate signaling proteins known to bind IRS‐1 and/or IRS‐2 via SH2 domain–mediated interactions (Nck, Grb‐2, fyn) in response to insulin, proteins with enzymatic activities that are stimulated by the action of phosphatidylinositol‐3′‐kinase (PI3K), or signaling pathways utilized in cells treated with insulin. These have not yet been shown to be involved in GH signal transduction. SHP2, SH2 domain containing tyrosine phosphatase; JAK, Janus kinase.

From 9, with permission


Figure 10.

Growth hormone (GH) stimulates a rapid, transient increase in diacylglycerol (DAG) in Ob1771 cells. Postconfluent Ob1771 cells maintained in standard medium were exposed to 5 nM GH (open squares) or 200 nM prostaglandin F2a (solid squares) for various times. Formation of DAG was measured. The basal value obtained in the absence of GH (3.5 nmol/1000 nmol of phospholipid) was subtracted from the reported values. Each value represents the mean of pooled triplicate wells (differences between determinations were < 20%). These results indicate that GH elicits a rapid, transient increase in DAG in Ob1771 cells.

From 69, with permission


Figure 11.

Growth hormone (GH) induces an increase in cytosolic Ca2+([Ca2+])i) in single INS‐1 cells. Changes in ([Ca2+]i were investigated in fura‐2‐loaded cells stimulated with 5 nM bovine GH (bGH) at 3 mM glucose in the absence (A) or presence (B) of 1 mM calciseptine. Cells were attached on glass coverslips and loaded with 1 mM fura‐2 acetoxymethyl ester for 30 min. [Ca2+]i was monitored by the measurement of 340:380 nm ratio during continuous perfusion with Krebs‐Ringer bicarbonate HEPES buffer containing 3 mM glucose as a basal condition. Stimuli were given through large‐orifice pipettes placed in the vicinity of the cell examined. Representative traces of those obtained in at least five cells are shown. These results demonstrate that GH induces a transient rise in intracellular Ca2+ levels in INS‐1 cells. The observation that the GH‐induced increase in [Ca2+]i is blocked by calciseptine suggests that, in these cells, GH activates voltage‐dependent, L‐type calcium channels.

From 264, with permission


Figure 12.

Growth hormone (GH), leukemia‐inhibitory factor (LIF), and interferon‐γ (IFNγ) induce tyrosyl phosphorylation of Stat1, Stat3, and Stat5 in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were incubated in the absence of hormone or with 23 nM (500 ng/ml) human GH, 25 ng/ml human LIF, or 10 ng/ml murine IFNγ, as indicated, for 15 min. Whole‐cell lysates were immunoprecipitated with antibodies to Stat1 (αStat1), Stat3 (αStat3), or Stat5 (αStat5), as indicated. Immunoprecipitated proteins were subjected to Western blot analysis using antiphosphotyrosine antibody. Migrations of Stat1, Stat3, and Stat5 are indicated. Signals observed in response to GH indicate that GH stimulates tyrosyl phosphorylation of Stats 1, 3, and 5. The differences in relative signal intensities for GH, LIF, and IFNγ for each Stat suggest that the requirements for activation differ for each Stat protein.

From 36, with permission


Figure 13.

Growth hormone (GH) promotes tyrosyl phosphorylation of Stat5A and Stat5B in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were incubated without hormone (‐) or with 23 nM (500 ng/ml) human GH (+) for 15 min. Stat5 proteins were immunoprecipitated with antibodies to Stat5A (αStat5A) or Stat5B (αStat5B). Immunoprecipitates (IP) were subjected to Western blot analysis using antiphosphotyrosine antibody (αPY), αStat5A, or αStat5B. Tyrosyl phosphorylation of both Stat5A and 5B was induced by GH, as evidenced by the increased signal observed in lanes B and D compared to lanes A and C. Multiple Stat bands exist even in the absence of GH (lane E), suggesting the presence of multiple serine or threonine phosphorylation states.

From 281, with permission


Figure 14.

Growth hormone (GH)–induced Sis‐inducible element (SIE)–binding complex contains Stat1 and Stat3. An electrophoretic mobility shift assay was performed using the human SIE probe and nuclear extracts prepared from 3T3–F442A cells stimulated for 30 min with vehicle (control, lane 1), GH (500 ng/ml, lanes 2–4), leukemia‐inhibitory factor (LIF; 65 ng/ml, lanes 5–7), or interferon‐γ (IFNγ, 10 ng/ml, lanes 8–10). Nuclear extracts were preincubated for 20 min at room temperature with antibodies to Stat1 (αStat1; lanes 3, 6, and 9) or Stat3 (αStat3; lanes 5, 7, and 10). Nuclear extracts were then incubated with the radiolabeled DNA probe and subjected to electrophoresis. The detection of three bands in lane 2 (bands A, B, and C) and the observation that these bands can be supershifted with antibodies to Stats 1 and 3 indicate that GH induces binding of Stat1‐and Stat3‐containing complexes to the SIE.

From 34, with permission


Figure 15.

Serum response element (SRE) mediates induction of c‐fos by growth hormone (GH). Cells (NIH‐3T3) were transiently transfected with fos promoter plasmids and the α‐globin expression plasmid to indicate transfection efficiency. At 64 h after transfection, quiescent cells were stimulated with GH (500 ng/ml), 10% calf serum (CS), or vehicle (C, control) for 30 min. Total RNA was analyzed by ribonuclease protection assay. Positions of the protected fragments representing the human c‐fos reporter (upper arrow), α‐globin (middle arrow), and endogenous mouse c‐fos (lower arrow) transcripts are indicated. Hela cell RNA (H) provides a reference for the human c‐fos transcripts. A: Stimulation by GH of SRE‐FOS containing a single copy of the c‐fos SRE upstream of a human c‐fos reporter (from 222 bp upstream of the transcription start site through the coding region). B: Lack of induction of the reporter alone. C: Lack of induction of a mutant SRE‐FOS containing the reporter under control of a mutated SRE, which fails to bind serum response factor.

From 85, with permission
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Article Title: Molecular Events in Growth Hormone–Receptor Interaction and Signaling
 

How to Cite

Lisa S. Smit, Debra J. Meyer, Lawrence S. Argetsinger, Jessica Schwartz, Christin Carter‐Su. Molecular Events in Growth Hormone–Receptor Interaction and Signaling. Compr Physiol 2011, Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth: 445-480. First published in print 1999. doi: 10.1002/cphy.cp070514