101.HGH Receptor Signaling

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101.HGH Receptor Signaling

 

 

 

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ABSTRACT……………………………………………………………………………………………………….. iii

AWKNOWLEDGMENTS ………………………………………………………………………………….. iv

LIST OF FIGURES…………………………………………………………………………………………….. vii

LIST OF ABBREVIATIONS ……………………………………………………………………………….. ix

CHAPTER 1. MOLECULAR EVOLUTION AND REGULATION OF GROWTH

HORMONE SIGNALING: TOWARD A HIGHLY INTEGRATED CONTROL

SYSTEM OF GROWTH ………………………………………………………………………………………..1

Introduction …………………………………………………………………………………………………..1

Molecular evolution and structure of GH signaling elements ………………………………2

Evolution by gene duplication ……………………………………………………………………..2

Molecular evolution and structure of the GH-family hormones ………………………..4

Molecular evolution of GH receptors ……………………………………………………………9

Molecular structure of the GH receptor family …………………………………………….14

Sources of variation in GH receptor structure ………………………………………………25

Differential and overlapping aspects of GH signaling………………………………………..30

Differential expression ………………………………………………………………………………30

Differential receptor binding characteristics …………………………………………………32

GH signal transduction and differential linkage to effector pathways ……………..33

GH signaling and the regulation of growth ……………………………………………………..36

A model of peripheral regulation ………………………………………………………………..37

GH regulated GHR expression …………………………………………………………………..38

GH as a means of integrating metabolism with growth ………………………………….42

Integration of growth with stress and osmoregulation…………………………………….44

Integration of growth with reproduction ………………………………………………………47

Summary and conclusions …………………………………………………………………………….48

Objectives of this thesis …………………………………………………………………………………51

References …………………………………………………………………………………………………..52

CHAPTER 2. EVOLUTIONARY ORIGIN AND DIVERGENCE OF THE

GROWTH HORMONE/PROLACTIN/SOMATOLACTIN RECEPTOR FAMILY:

INSIGHTS FROM STUDIES IN SEA LAMPREY…………………………………………………..74

Introduction …………………………………………………………………………………………………74

Materials and methods ………………………………………………………………………………….78

Experimental animals ……………………………………………………………………………….78

RNA extraction ………………………………………………………………………………………..78

Oligonucleotide primers and probes ……………………………………………………………79

Isolation and characterization of putative GHR-like mRNA …………………………..79

Real-time PCR assay; quantification of GHR-encoding mRNA ……………………..81

Data analysis ……………………………………………………………………………………………82

Results and discussion ………………………………………………………………………………….83

Characterization of GHR-like mRNA …………………………………………………………83

Evolution of the GHRs ……………………………………………………………………………..94

Structural assessment of the family of receptors for GH, PRL, and SL ……………96

Summary and conclusions ………………………………………………………………………….110

References ………………………………………………………………………………………………..115

CONCLUDING REMARKS AND FUTURE DIRECTIONS ………………………………….123

General remarks and comments on the future direction of this research ……………123

References ………………………………………………………………………………………………..125

HGH Receptor Signaling


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.


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 (Figure1).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 (Table1).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 (Figure2)2) (6, 7). This provides a scaffold for binding of STAT5a and STAT5b, which are subsequently phosphorylated by JAK2 upon receptor docking (Figure (Figure3)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) is a critical regulator of linear body growth during childhood but continues to have important metabolic actions throughout life. The GH receptor (GHR) is ubiquitously expressed, and deficiency of GHR signaling causes a dramatic impact on normal physiology during somatic development, adulthood, and aging. GHR belongs to a family of receptors without intrinsic kinase activity. However, GH binding to homodimers of GHR results in a conformational change in the receptors and the associated tyrosine kinase Janus kinase 2 (JAK2) molecules. Activated JAK2 phosphorylates the GHR cytoplasmic domain on tyrosine residues, and subsequent JAK2-dependent and JAK2-independent intracellular signal transduction pathways evoke cell responses including changes in gene transcription, proliferation, cytoskeletal reorganization, and lipid and glucose metabolism. JAK2 phosphorylates STAT5b, which is a key transcription factor in GH regulation of target genes associated with body growth, intermediate metabolism, and gender dimorphism; although STAT1, 3, and 5a have also been shown to be recruited by the GHR. In addition, many transcripts are regulated independently of STAT5b as a result of GHR activation of Src, ERK, and PI3K-mTOR signaling pathways. The analysis of molecular mechanisms involved in inactivation of GHR-dependent signaling pathway is also imperative for understanding GH physiology. This is clearly illustrated in the case of hepatic GHR-JAK2-STAT5b activation where signal duration regulates gender differences in liver gene expression. An early step in the termination of GH-dependent signaling is removal of GHRs by endocytosis and ubiquitination. The level of ubiquitin ligase SOCS2 is constitutively low, but its expression is rapidly induced by GH. SOCS2 binding to GHR complex promotes their ubiquitination and subsequent proteasomal degradation, contributing to the termination of the GH intracellular signaling. Clinically relevant, SOCS2 is a key negative regulator of GH-dependent body growth and lipid and glucose homeostasis. Furthermore, several cytokines, growth factors, xenobiotics, and sex hormones can regulate SOCS2 protein level, which provides a mechanism for cross-talking where multiple factors can regulate GHR signaling during somatic development. A better understanding of this complex regulation in physiological and pathological states will contribute to prevent health damage and improve clinical management of patients with growth and metabolic disorders.


Growth hormone (Somatotropin or GH) is a key factor in determining lean body mass, stimulating the growth and metabolism of muscle, bone and cartilage cells, while reducing body fat. It has many other roles; it acts to regulate cell growth, differentiation, apoptosis, and reorganisation of the cytoskeleton, affecting diverse processes such as cardiac function, immune function, brain function, and aging. GH also has insulin-like effects such as stimulating amino acid transport, protein synthesis, glucose transport, and lipogenesis. The growth hormone receptor (GHR) is a a member of the cytokine receptor family. When the dimeric receptor binds GH it undergoes a conformational change which leads to phosphorylation of key tyrosine residues in its cytoplasmic domains and activation of associated tyrosine kinase JAK2. This leads to recruitment of signaling molecules such as STAT5 and Src family kinases such as Lyn leading to ERK activation. The signal is attenuated by association of Suppressor of Cytokine Signaling (SOCS) proteins and SHP phosphatases which bind to or dephosphorylate specific phosphorylated tyrosines on GHR/JAK. The availability of GHR on the cell surface is regulated by at least two processes; internalization and cleavage from the suface by metalloproteases.


GHR and GHBP
Growth hormone receptors (GHRs) have been found on the cell surfaces of many tissues throughout the body, including liver, muscle, adipose, and kidney, and in early embryonic and fetal tissue. Although most GHRs reside on the cell surface and in the endoplasmic reticulum, pronounced nuclear localization is noted in many cells.64 Evidence for the importance of the GHR in growth has come from studies on individuals expressing different mutations located throughout the GHR gene that result in the dwarf phenotype and a GH-insensitive state.


The GHR is a member of the class 1 hematopoietic cytokine family. The human GHR gene encompasses 10 exons and approximately 90 kb, and encodes an extracellular domain, a small transmembrane domain, and an intracellular domain. The protein-coding region of the GHR gene is encoded by exons 2 through 10. Exon 2 of the GHR gene encodes the secretory signal peptide and the first six amino acids of the mature form of the protein; exons 3 through 7 encode the extracellular domain, exon 8 the transmembrane domain, and exons 9 and 10 the intracellular domain.


The extracellular portion of the GHR consists of two fibronectin type III domains, each containing seven β-strands, arranged to form a sandwich of two antiparallel β-sheets.39 Stabilizing the GHR structure is a salt bridge between Arg 39 and Asp 132, and hydrogen bonds between Arg 43 and Glu 169.39 Also, the GHR contains seven cysteine residues in its extracellular domain39; the six in the GH binding domain form three disulfide bonds in the active signaling conformation, and help the receptor to maintain its correct structure.65 Van den Eijnden and coworkers have suggested, after studying the effects of replacing the Cys with Ser and Ala residues, that the middle disulfide bond, Cys83-Cys94, is important for ligand binding, whereas removal of disulfide bond Cys108-Cys122 has little effect on GH-induced intracellular signaling.65 The GHR has a cellular half-life of approximately 1 hour and is internalized and degraded continuously, even in the absence of GH through two known mechanisms: endocytosis and ectodomain cleavage. Excellent reviews of the molecular aspects of the GHR have been published and are cited here.


In addition to the membrane-bound GHR, a soluble form exists that is composed of a portion of the extracellular domain, GHBP. In mice and rats, GHBP is encoded by an additional exon of the GHR gene, namely Exon 8A, and is produced by alternative splicing of the GHR precursor mRNA. In other vertebrates, it is generated by proteolytic cleavage of the extracellular domain of the GHR. A metalloprotease tumor necrosis factor (TNF)-α converting enzyme (TACE/ADAM-17) has been reported to act on surface GHR to generate the GHBP.67 The function of the GHBP is not fully understood, but it may modulate GH activity by enhancing its serum half-life or reducing its availability to bind the GHR. The reader is referred to a review paper on GHBPs for further information.

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