The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects

Abstract

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.

Keywords: Janus kinase 2; Src family kinase; growth hormone; growth hormone receptor; insulin-like growth factor 1; suppressor of cytokine signaling.

Figure 1

The growth hormone receptor domain organization.

Figure 2

Activation of the growth hormone receptor (GHR) by growth hormone. In the inactive homodimeric GHR, (A) the Janus kinase (JAK) 2 kinase domain (KD) is inhibited in trans by interaction with the pseudokinase domain from the JAK2 bound to the opposing receptor within the homodimer. GH binding to the GHR extracellular domain (B) results in conformational changes that cause the transmembrane domains to transition from a parallel interaction to a left-handed crossover interaction. These structural changes cause a separation of the intracellular domains to the Box1 and Box2 motifs and the associated JAK2 molecules. The movement of the associated JAK2s dissociates the inhibitory interaction of the pseudokinase from the KD and brings the two JAK2 KDs in close proximity resulting in trans phosphorylation and activation.

Figure 3

The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling pathway initiated by the activated growth hormone receptor. Activated JAK2 phosphorylates tyrosines on the intracellular domain of the receptor. Inactive-STAT5 dimers bind these phosphorylated tyrosine residues on the receptor, and the STAT5 is subsequently phosphorylated by JAK2 forming different active-STAT5 dimers that are translocated to the nucleus, bind DNA, and act as transcription factors. STAT1 and STAT3 are phosphorylated and activated by JAK2. Active STAT1 and STAT3 form homodimers or heterodimers, are translocated to the nucleus, bind DNA, and act as transcription factors.

Figure 4

The Src family kinase (SFK) signaling initiated by the activated growth hormone receptor (GHR). SFKs are activated by GH binding to GHR. This signaling pathway activates ERK1/2 that regulates cytosolic targets and gene transcription.

Figure 5

The major negative regulation of growth hormone receptor (GHR) signaling. GH-activated GHR results in suppressor of cytokine signaling (SOCS) 2 binding to a phosphorylated tyrosine on the GHR intracellular domain. This blocks signal transducer and activator of transcription (STAT) 5 binding and induces ubiquitination of the GHR leading to targeted degradation of the receptor. SHP1 and SHP2 act to dephosphorylate and inactivate Janus kinase 2 and STATs, while SHP2 is known to also dephosphorylate the receptor.

Figure 6

Organ-specific roles of the GH/insulin-like growth factor-1 (IGF-1) axis.