FIGURE 2 (A) Typical growth curves for boys and girls. Note that growth is not strictly linear and that it proceeds at the same rate in juvenile boys and girls. At puberty, which begins earlier in girls than in boys, a spurt in growth immediately precedes growth arrest. (B) Nonlinearity of growth is more clearly evident when plotted as the changes in growth rate over time. Note that growth, which is vary rapid in the newborn, slows during the juvenile period and accelerates at puberty.

similar growth-promoting activity, although metabolic effects of the 20K form are reduced.

About half of the GH in blood circulates bound to a protein that has the same amino acid sequence as the extracellular domain of the GH receptor (see below). In fact, the plasma GH binding protein is a product of the same gene that encodes the GH receptor and originates by proteolytic cleavage of the receptor at the outer surface of target cells. It is thought that the binding protein serves as a reservoir of GH that buffers changes in free hormone concentration and prolongs the half-life of the hormone. The monomeric form of free GH can readily cross capillary membranes, but bound hormone presumably cannot. The half-life of GH in blood is about 20 min. GH that crosses the glomerular membrane is reabsorbed and destroyed in the kidney, which is the major site of GH degradation. Less than 0.01% of the hormone secreted each day reaches the urine in recognizable form. GH is also degraded in its various target cells following uptake by receptor mediated endocytosis.

Mode of Action

Like other peptide and protein hormones, GH binds to its receptor on the surface of target cells. The GH receptor is a glycoprotein that has a single membrane-spanning region and a relatively long intracellular tail; it neither has catalytic activity nor interacts with G proteins. The GH receptor binds to a cytosolic enzyme called Janus kinase 2 (JAK-2), which catalyzes the phosphorylation of the receptor and other proteins on tyrosine residues (see Chapter 2). Growth hormone activates a signaling cascade by binding sequentially to two GH receptor molecules to form a receptor dimer that sandwiches the hormone between the two receptor molecules. Such dimerization of receptors is also seen for other hormone and cytokine receptors of the super-family to which the GH receptor belongs. Dimerization of receptors brings the bound JAK-2 enzymes into favorable alignment to promote tyrosine phosphorylation and activation of their catalytic sites. In addition, dimeriza-tion may also recruit JAK-2 molecules to unoccupied binding sites on the receptors. Tyrosine phosphorylation provides docking sites for other proteins and facilitates their phosphorylation. One group of target proteins, called STATs (signal transducers and activators of transcription), migrate to the nucleus, and activate gene transcription (see Chapter 2). Another target group, the mitogen-activated protein (MAP) kinases, are also thought to have a role in promoting gene transcription. Activation of the GH receptor also results in an influx of extracellular calcium through voltage-regulated channels which may further promote transcription of target genes. All in all, GH produces its effects in various cells by stimulating the transcription of specific genes.

Effects on Skeletal Growth

The ultimate height attained by an individual is determined by the length of the skeleton and, in

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