87.Growth Hormone Signal Transduction

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87.Growth Hormone Signal Transduction

 

 

 

CATEGORY: Anabolic Steroids 100 Courses

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Syllabus

Dedication …………………………………………………………………………………………………………………….. ii
Acknowledgements ………………………………………………………………………………………………………. iii
List of Figures………………………………………………………………………………………………………………. ix
Abstract……………………………………………………………………………………………………………………….. xi
Chapter 1 ……………………………………………………………………………………………………………………….1
Introduction………………………………………………………………………………………………………………..1
Growth Hormone Signal Transduction…………………………………………………………………………..1
GH receptor dimerization and activation………………………………………………………………………..2
GH signal transduction via JAK2 ………………………………………………………………………………….5
GH signal transduction via Src tyrosine kinase ……………………………………………………………….6
GH regulation of Stat transcription factors……………………………………………………………………..8
GH signal transduction via MAPK and PI3-kinase pathways………………………………………….12
Negative regulators of GH signaling ……………………………………………………………………………14
Receptor processing and subcellular localization…………………………………………………………..18
SH2B1 in GH Signal Transduction………………………………………………………………………………21
SH2B1 as a JAK2 binding protein……………………………………………………………………………..22
SH2B1 in GH-induced regulation of the actin cytoskeleton ………………………………………….23
Thesis Summary …………………………………………….. 30
Chapter 2 ……………………………………………………………………………………………………………………..37

JAK2, but not Src family kinases, is required for Stat, ERK, and Akt signaling
in response to growth hormone in 3T3-F44A preadipocyte and H4IIE hepatoma
cells………………………………………………………………………………………………………………………………37

Abstract……………………………………………………………………………………………………………………37
Introduction………………………………………………………………………………………………………………39
Results……………………………………………………………………………………………………………………..42
Discussion………………………………………………………………………………………………………………..61
Materials and Methods……………………………………………………………………………………………….69
Acknowledgements……………………………………………………………………………………………………73
Chapter 3 ……………………………………………………………………………………………………………………..74
Growth hormone induces SH2B1 and JAK2 to form a complex with the
novel SH2B1-interacting partner, II-spectrin, and induces II-spectrin
re-localization ………………………………………………………………………………………………………………..74
Abstract……………………………………………………………………………………………………………………74
Introduction………………………………………………………………………………………………………………76
Results……………………………………………………………………………………………………………………..79
Discussion………………………………………………………………………………………………………………..94
Materials and Methods……………………………………………………………………………………………….97
Acknowledgements………………………………………………………………………………………………….101
Chapter 4 ……………………………………………………………………………………………………………………102
Identification and characterization of SH2B1 as a novel focal adhesion protein…………….102
Abstract………………………………………………………………………………………………………………….102

Introduction…………………………………………………………………………………………………………….104
Results……………………………………………………………………………………………………………………107
Discussion………………………………………………………………………………………………………………122
Materials and Methods……………………………………………………………………………………………..127
Chapter 5 ……………………………………………………………………………………………………………………131
Conclusion ……………………………………………………………………………………………………………..131
Summary………………………………………………………………………………………………………………..163
References…………………………………………………………………………………………………………………..164

 

Growth Hormone Signal Transduction


Multiple signaling pathways mediate the diverse effects of growth hormone (GH) on growth and metabolism. The interaction of GH with GH receptors (GHR) on target cells promotes the association of the cellular tyrosine kinase JAK2 with the GHR, initiating tyrosine phosphorylation of GHR and JAK2, and activation of multiple signaling cascades. GH-stimulated activation of signal transducers and activators of transcription (STATs), mitogen activated protein kinase (MAPK) and phosphatidylinositol 3′ kinase (PI3K) cascades have been shown to regulate the transcription of GH-responsive genes. Cross-talk among these signaling cascades in regulating specific genes suggests that GH signaling to the nucleus involves a GH-regulated signaling network.


The growth hormone receptor (GHR), although most well known for regulating growth, has many other important biological functions including regulating metabolism and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. In addition, growth hormone signaling is an important regulator of aging and plays a significant role in cancer development. Growth hormone activates the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling pathway, and recent studies have provided a new understanding of the mechanism of JAK2 activation by growth hormone binding to its receptor. JAK2 activation is required for growth hormone-mediated activation of STAT1, STAT3, and STAT5, and the negative regulation of JAK–STAT signaling comprises an important step in the control of this signaling pathway. The GHR also activates the Src family kinase signaling pathway independent of JAK2. This review covers the molecular mechanisms of GHR activation and signal transduction as well as the physiological consequences of growth hormone signaling.


Introduction
The growth hormone receptor (GHR) is a member of the class I cytokine receptor family, which includes more than 30 receptors such as the prolactin receptor (PRLR), erythropoietin receptor (EPOR), thrombopoietin receptor (TPOR), granulocyte-macrophage colony-stimulating factor receptor, interleukin-3 receptor, interleukin-6 receptor, and interleukin-7 receptor (1, 2). GHR has been considered the archetypal class I cytokine receptor as it was the first cytokine receptor to be cloned and have its extracellular domain (ECD) crystal structure solved (3). GHR is a 638 amino acid long homodimeric receptor with one cytokine receptor homology domain (CRH), a single-pass transmembrane domain, and cytoplasmic intracellular domain (ICD) (Figure 1). With the exception of GHR, all members of the class I cytokine receptor family contain a WSXWS motif in the ECD. The WSXWS motif is important for expression and stability of the receptor and comprises a consensus sequence for C-mannosylation. For the IL-21R, the WSXWS has been shown to be mannosylated at the first tryptophan where the sugar chain appears to form structurally important interactions that bridge the two fibronectin domains (4, 5). GHR has in place of the WSXWS a similar sequence of YGeFS that has an analogous function in expression and stability of the receptor (1). Cytokine receptors lack an intrinsic protein tyrosine kinase (PTK) activity and therefore rely on binding non-receptor PTKs for their signal transduction. Within the ICD of all class I cytokine receptors is a proline-rich Box1 motif that is located a short distance from the cell membrane. A less conserved Box2 sequence consisting of acidic and aromatic residues is located a short distance C-terminal of the Box1 (1). The Box1 motif acts as a binding site for a cognate Janus kinase (JAK) of which there are four family members, JAK1, JAK2, JAK3, and TYK2 that can bind to specific receptors (Table 1). For GHR, the only JAK family member that binds the receptor is JAK2. GH binding to GHR results in activation of JAK2, which subsequently phosphorylates multiple tyrosine residues on the ICD of the receptor (Figure 2) (6, 7). This provides a scaffold for binding of STAT5a and STAT5b, which are subsequently phosphorylated by JAK2 upon receptor docking (Figure 3) (8). GHR also activates STAT1 and STAT3 via JAK2; however, these STATs do not appear to require binding to the phosphorylated receptor. Other signaling pathways such as the Ras/extracellular signal-regulated kinase (ERK) and PI 3-kinase/Akt are also activated by GHR (7, 9). The consequence of these GH-mediated cellular signaling pathways in a diverse range of cell types is responsible for the large range of physiological processes regulated by GH.


Growth hormone (GH) promotes animal growth by stimulating bone and cartilage cell proliferation, and influences carbohydrate and lipid metabolism. Some of these effects are brought about indirectly via somatomedin induction in hepatocytes, others by acting directly on the target cells. In either case, GH first binds to specific receptors on cells to trigger a sequence of biochemical events culminating in a biological response. Recently much has been learnt about the molecular structure of GH receptor, its binding to ligand, and the ensuing signal transduction events.

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