Growth hormone signaling pathways
Introduction
For many years, growth hormone (GH) has been known to be the primary hormone responsible for body growth. The tallest man on record (http://www.guinnessworldrecords.com/world-records/tallest-man-ever/), Robert Wadlow, had an untreated pituitary tumor that secreted abnormally high levels of GH [7]. He grew throughout life, achieving a height of 8 ft., 11 in. at the time of his death. Even today, the tallest people on record tend to achieve their great heights due to untreated pituitary tumors. The reverse is also true. Individuals who, for whatever reason, do not make normal levels of GH as children or have defective GH receptors, are short statured [14]. GH has also been recognized to regulate carbohydrate, protein and lipid metabolism. For example, GH decreases fat and increases lean body mass [16].
Section snippets
GH binding to its receptor activates the tyrosine kinase JAK2
In the mid 1980s, we asked the question of how GH acted at the level of the cell to bring about its diverse responses on body growth and metabolism. The GH receptor had been shown to be a membrane receptor that migrated as an ~ 110 kDa protein [11]. It was also known that defective GH receptors (patients with Laron Syndrome) resulted in short stature [20]. However, nothing was known about the signal transduction events that enabled GH binding to its plasma membrane-bound receptor to direct
JAK2 activation initiates signaling via multiple pathways
Having identified JAK2 as a critical and initiating cell signaling event for GH, we set out to determine the signaling events that are initiated as a consequence of JAK2 activation (Fig. 1). The first protein that caught our attention was p91, a transcription factor that had been identified in the context of the immune system. P91 was an intriguing candidate because of the finding that interferon (IFN)γ and IFNα, both of which were known to activate p91 [21], [28], [48], [49] had recently been
JAK2 interacts with the scaffold protein SH2B1
To identify novel GH signaling proteins that are activated as a consequence of GH activation of JAK2, we performed a yeast 2-hybrid assay using the C-terminal amino acids of JAK2, which contains the kinase domain. When expressed in yeast, this portion of JAK2 is constitutively active. Of the potential JAK2 binding proteins identified in this assay, the adapter protein SH2B1 (SH2-B, PSM) was the most intriguing [47]. We pulled out the C-terminal 143 amino acids of a previously unidentified
SH2B1 regulates the actin cytoskeleton and cell motility
We have identified several other functions of SH2B1. When we observed the subcellular localization of GFP-tagged SH2B1, we found that SH2B1β localizes to membrane ruffles in cultured fibroblasts [24]. Membrane ruffles are formed at the leading edge of motile cells. This led us to hypothesize that SH2B1 interacts with and regulates the actin cytoskeleton. In support of this, we found that overexpressing SH2B1β increases membrane ruffling and cell motility in response to GH [18], [24]. We next
Growth hormone signaling pathways implicated in humans
Among the GH signaling proteins identified in these in vitro studies, only the GH receptor and Stat5b have been shown by human mutations to be associated with short stature in humans [20], [27]. However, it is interesting to note that individuals with mutations in the IRS-1/PI3K pathway are short [15] as are individuals with RASopathies, which are diseases due to mutations in proteins in the MAP kinase pathway [57]. Some of the latter individuals are GH-deficient. Whether impaired GH signaling
Summary
We have shown that GH binding to its receptor activates the GH receptor associated JAK2 tyrosine kinase. JAK2 in turn phosphorylates tyrosines within the GH receptor and within itself. These phosphorylated tyrosines can then recruit signaling proteins to GH receptor–JAK2 complexes in the plasma membrane. Proteins recruited to GH receptor–JAK2 complexes and phosphorylated by JAK2 include the transcription factors Stats 1, 3, 5a, and 5b that regulate GH sensitive genes including genes encoding
Conflict of interest
There are no conflicts of interest.
Acknowledgements
This work was supported by grants from the National Institutes of Health (R01-DK54222 to CCS, R01-DK46072 to JS). We wish to acknowledge the help of Debbra Tackett and Joel Cline with manuscript preparation.
References (69)
On the diabetogenic effect of growth hormone in man: effects of growth hormone of glucagon and insulin secretion
Eur. J. Clin. Investig.
(1981)- et al.
Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Ba
Curr. Biol.
(1997) - et al.
Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase
Cell
(1993) - et al.
Growth hormone, interferon-γ, and leukemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate-1
J. Biol. Chem.
(1995) - et al.
Growth hormone, interferon-γ, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling
J. Biol. Chem.
(1996) A novel family of growth factor receptors: a common binding domain in the growth hormone, prolactin, erythropoietin and IL-6 receptors, and the p75 IL-2 receptor B-chain
Biochem. Biophys. Res. Commun.
(1989)- et al.
Hyperpituitarism beginning in infancy: the alton giant
Endocrinology
(1932) - et al.
Large, rare chromosomal deletions associated with severe early-onset obesity
Nature
(2010) - et al.
Activation of acute phase response factor (APRF)/Stat3 transcription factor by growth hormone
J. Biol. Chem.
(1995) - et al.
Rapid and transitory stimulation of 3-O-methylglucose transport by growth hormone
Am. J. Physiol.
(1988)