Signaling via JAK tyrosine kinases: growth hormone receptor as a model system
1Department of Physiology, University of Michigan Medical School, Ann Arbor 48109-0622, USA.
Abstract:
During the past 4 years, significant progress has been made in elucidating the earliest events following binding of ligands to members of the cytokine receptor superfamily. This is a rapidly growing family of receptors that currently includes receptors for growth hormone (GH); prolactin; erythropoeitin; granulocyte colony-stimulating factor; granulocyte macrophage colony-stimulating factor; interleukin(IL)s 2-7, 9-13, 15; interferon (IFN)-alpha, beta, and gamma; thrombopoietin; leptin; oncostatin M; leukemia inhibitory factor (LIF); ciliary neurotrophic factor; and cardiotropin-1. Despite their diverse physiological effects in the body, ligands that bind to members of this family share multiple signaling pathways. An early and most likely initiating event for all of them is the activation of one or more members of the Janus (or JAK) family of tyrosine kinases. The activated JAK kinases, which form a complex with the cytokine receptor subunits, phosphorylate themselves as well as the receptor. These phosphorylated tyrosines form binding sites for various signaling molecules that are themselves thought to be phosphorylated by JAK kinases, including 1) signal transducers and activators of transcription (Stats), which regulate transcription; 2) She proteins that recruit Grb2-SOS complexes, thereby initiating the Ras-MAP kinase pathway; and 3) insulin receptor substrate (IRS) proteins that are thought to regulate metabolic events in the cell. Additional other signaling molecules have been implicated in signaling by some cytokines, including protein kinase C, SH2-B beta, and intracellular Ca. This review uses the GH receptor as a model system for studying cytokine signaling and summarizes some of the data used to establish JAK2 as a GH receptor-associated tyrosine kinase and to identify signaling molecules that lie downstream of JAK2. Since these pathways are shared by multiple cytokines, this review also discusses factors that might contribute to specificity of response to different cytokines.
Insights
Cytokine receptor superfamily signaling begins with Janus (JAK) kinase activation. This initiates downstream pathways involving STATs, Ras-MAP kinase, and insulin receptor substrates, crucial for diverse cellular responses.
Area of Science:
- Molecular Biology
- Cell Signaling
- Biochemistry
Background:
- The cytokine receptor superfamily encompasses numerous receptors with diverse physiological roles.
- Ligand binding to these receptors triggers shared intracellular signaling pathways.
- Janus kinases (JAKs) are early and critical mediators in these signaling cascades.
Purpose of the Study:
- To elucidate the earliest signaling events following ligand binding to cytokine receptors.
- To review the role of JAK kinases in cytokine receptor activation.
- To identify downstream signaling molecules and understand specificity in cytokine responses.
Main Methods:
- Utilizing the growth hormone (GH) receptor as a model system.
- Summarizing data establishing JAK2 as a GH receptor-associated tyrosine kinase.
- Identifying signaling molecules downstream of JAK2 activation.
Main Results:
- JAK kinase activation is an initiating event for cytokine receptor superfamily signaling.
- Activated JAKs phosphorylate themselves and the receptor, creating binding sites for signaling molecules.
- Downstream molecules include STATs, She proteins (leading to Ras-MAP kinase pathway), and IRS proteins.
Conclusions:
- JAK2 is a key tyrosine kinase associated with the GH receptor.
- Understanding these shared pathways is essential for deciphering cytokine-specific responses.
- Further research into these signaling networks can reveal mechanisms of cellular specificity.
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