Growth hormone signaling pathways

Abstract

Over 20years ago, our laboratory showed that growth hormone (GH) signals through the GH receptor-associated tyrosine kinase JAK2. We showed that GH binding to its membrane-bound receptor enhances binding of JAK2 to the GHR, activates JAK2, and stimulates tyrosyl phosphorylation of both JAK2 and GHR. The activated JAK2/GHR complex recruits a variety of signaling proteins, thereby initiating multiple signaling pathways and cellular responses. These proteins and pathways include: 1) Stat transcription factors implicated in the expression of multiple genes, including the gene encoding insulin-like growth factor 1; 2) Shc adapter proteins that lead to activation of the grb2-SOS-Ras-Raf-MEK-ERK1,2 pathway; 3) insulin receptor substrate proteins implicated in the phosphatidylinositol-3-kinase and Akt pathway; 4) signal regulatory protein α, a transmembrane scaffold protein that recruits proteins including the tyrosine phosphatase SHP2; and 5) SH2B1, a scaffold protein that can activate JAK2 and enhance GH regulation of the actin cytoskeleton. Our recent work has focused on the function of SH2B1. We have shown that SH2B1β is recruited to and phosphorylated by JAK2 in response to GH. SH2B1 localizes to the plasma membrane, cytoplasm and focal adhesions; it also cycles through the nucleus. SH2B1 regulates the actin cytoskeleton and promotes GH-dependent motility of RAW264.7 macrophages. Mutations in SH2B1 have been found in humans exhibiting severe early-onset childhood obesity and insulin resistance. These mutations impair SH2B1 enhancement of GH-induced macrophage motility. As SH2B1 is expressed ubiquitously and is also recruited to a variety of receptor tyrosine kinases, our results raise the possibility that effects of SH2B1 on the actin cytoskeleton in various cell types, including neurons, may play a role in regulating body weight.

Keywords: Growth hormone; JAK2; SH2B1; Signal transduction.

Fig. 1.

GH acts via a variety of signal transduction pathways. GH: growth hormone; GHR: growth hormone receptor; JAK2, Janus kinase 2; STAT: Signal Transducer and Activator of Transcription; MAPK: mitogen-activated protein kinase; IRS: insulin receptor substrate; PI3K: phosphatidyl inositol 3 kinase. Figure adapted from C Carter-Su, L Rui, J Herrington, M Stofega and M Diakonova, 2001, Targets for Growth Hormone and IGF-1 Action, pp31–43 © Bioscientifica Ltd. Adapted by permission.

Fig. 2.

Multiple GH signaling pathways can contribute to specific GH responses. GH: growth hormone; GHR: growth hormone receptor; JAK2, Janus kinase 2; STAT: Signal Transducer and Activator of Transcription; MAPK: mitogen-activated protein kinase; IRS: insulin receptor substrate; PI3K: phosphatidyl inositol 3 kinase; GSK-3: glycogen synthase kinase-3; TCF: ternary complex factors; SRF: serum response factor; C/EBP: CCAAT enhancer binding protein. Figure adapted from Cesena et al., Molecular Genetics and Metabolism, 2007, 90, 126–133 © Bioscientifica Ltd (2007). Adapted by permission.

Fig. 3.

SH2B1β regulates the actin cytoskeleton and cell motility at least in part by serving as a scaffold protein for actin cytoskeleton-regulating proteins.