Cytokine Signaling

Cytokine signaling is an important part of the human body regulation. Most cytokines are cell-secreted proteins from glial cells in the nervous system and are necessary for intracellular signaling. Most cytokines are local regulators that alert and activate lymphocytes. Some cytokine-signaling pathways involve hormones such as growth hormones and leptin, the hormone that controls fat storage.

The immune system depends on cytokine signaling to keep the human body healthy. Macrophages and dendritic cells engulf foreign particles and send a cytokine signal to nearby dormant lymphocytes. The receptors on the lymphocytes recognize the signal and activate. Those cells are specialized to recognize certain antigens. The combination of the macrophages and activation of lymphocytes through cytokine signaling help keep the body in homeostasis — or the proper internal equilibrium.

Some cytokine signals are not local but rather travel a long distance throughout the body. These cytokines are sometimes classified as hormones. This classification is changing, however, because cytokines are not secreted from glands. Instead, they are secreted from glial cells of the nervous system. These growth hormones are essential for embryonic development. Cytokines bind to receptors on target cells and activate a cascade of intercellular signals. The most common of these pathways is the protein kinase transduction cascade. After the cytokine binds to the receptor embedded in the membrane of the cell, inactive protein kinases are activated by a process known as phosphorylation.

Cytokine signaling pathway

Cytokine receptors contain one to three chains, one or more of which generally have limited similarity in the membrane-proximal region (often referred to as box1/box2 motifs). According to the nomenclature the ligand-binding subunit of a receptor is referred to as the alpha chain. Other signal transducing subunits are named beta chains, or gamma chains. All cytokine receptors are associated with one or more members of JAKs, which couple ligand binding to tyrosine phosphorylation of various signaling proteins (STATs) recruited to the receptor complex.

Molecular cloning of cytokine receptors and subsequent structure–function studies has revealed that unlike growth factor receptors, cytokine receptors are devoid of catalytic activity. Nevertheless, interaction of a cytokine with its receptor rapidly induces tyrosine phosphorylation of the receptor and a variety of cellular proteins, suggesting that these receptors transmit their signals through cellular tyrosine kinases. During the past 10–15 years, a large amount of experimental data have accumulated to indicate that most cytokines transmit their signals via a distinct family of tyrosine kinases termed Janus kinases or JAKs.

Cytokine receptors activate many signaling pathways generally by means of phosphotyrosine residues, which are recognized by SH2 domains on the signaling molecules. The STATs contain a carboxy-terminal SH2 domain, an SH3-like domain and several conserved amino-terminal regions, and a conserved region in the middle of the protein that binds DNA. Tyrosine phosphorylation of a carboxy-terminal site mediates homo- or heterodimerization through the SH2 domains, triggering movement to the nucleus and DNA binding.

A native un-liganded receptor in complex with a JAK is in a catalytically inactive latent state. Receptor dimerization/oligomerization due to ligand binding results in the juxtapositioning of the JAKs, which are in the vicinity through either homo- or heterodimeric interactions. The recruitment of JAKs appears to result in their phosphorylation, either via autophosphorylation and/or cross phosphorylation by other JAKs or via other families of tyrosine kinases. This activation is presumed to result in increased JAK activity. Activated JAKs then phosphorylate receptors on target tyrosine sites. The phosphotyrosine sites on the receptors can then serve as docking sites that allow the binding of other SH2-domain containing signaling molecules such as STATs, Src-kinases, protein phosphatases and other adaptor signaling proteins such as Shc, Grb2 and phosphatidylinositol 3-kinase (PI3K).