Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

Abstract

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 JAK2dependent 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.