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Cytokine Receptors and the JAK-STAT Pathway

We turn now to a second important class of cell-surface receptors, the cytokine receptors, whose cytosolic domains are closely associated with a member of a family of cy-tosolic protein tyrosine kinases, the JAK kinases. A third class of receptors, the receptor tyrosine kinases (RTKs), contain intrinsic protein tyrosine kinase activity in their cytosolic domains. The mechanisms by which cytokine receptors and receptor tyrosine kinases become activated by ligands are very similar, and there is considerable overlap in the intracellular signal-transduction pathways triggered by activation of receptors in both classes. In this section, we first describe some similarities in signaling from these two receptor classes. We then discuss the JAK-STAT pathway, which is initiated mainly by activation of cytokine receptors.

Cytokine Receptors and Receptor Tyrosine Kinases Share Many Signaling Features

Ligand binding to both cytokine receptors and RTKs triggers formation of functional dimeric receptors. In some cases, the ligand induces association of two monomeric

▲ FIGURE 14-4 Dimerization of the receptor for epidermal growth factor (EGF), a receptor tyrosine kinase. (a) Schematic depiction of the extracellular and transmembrane domains of the EGF receptor. Binding of one EGF molecule to a monomeric receptor causes an alteration in the structure of a loop located between the two EGF-binding domains. Dimerization of two identical ligand-bound receptor monomers in the plane of the membrane occurs primarily through interactions between the two "activated" loop segments. (b) Structure of the dimeric EGF receptor's extracellular domain bound to transforming growth factor a (TGFa), a homolog of EGF. The EGF receptor extracellular domains are shown in white (left) and blue (right). The two smaller TGFa molecules are colored green. Note the interaction between the "activated" loop segments in the two receptors. [Part (a) adapted from J. Schlessinger, 2002, Cell 110:669; part (b) from T Garrett et al., 2002, Cell 110:763.]

receptor subunits diffusing in the plane of the plasma membrane (Figure 14-4). In others, the receptor is a dimer in the absence of ligand, and ligand binding alters the conformation of the extracellular domains of the two sub-units. In either case, formation of a functional dimeric receptor causes one of the poorly active cytosolic kinases to phosphorylate a particular tyrosine residue in the activation lip of the second kinase. This phosphorylation activates kinase activity and leads to phosphorylation of the second kinase in the dimer, as well as several tyrosine

▲ FIGURE 14-5 General structure and ligand-induced activation of receptor tyrosine kinases (RTKs) and cytokine receptors. The cytosolic domain of RTKs contains a protein tyrosine kinase catalytic site, whereas the cytosolic domain of cytokine receptors associates with a separate JAK kinase (step 1). In both types of receptor, ligand binding causes a conformational change that promotes formation of a functional dimeric receptor, bringing together two intrinsic or associated residues in the cytosolic domain of the receptor (Figure 14-5). As we see later, phosphorylation of residues in the activation loop is a general mechanism by which many kinases are activated.

Certain phosphotyrosine residues formed in activated cytokine receptors and RTKs serve as binding, or "docking," sites for SH2 domains or PTB domains, which are present in a large array of intracellular signal-transduction proteins.

kinases, which then phosphorylate each other on a tyrosine residue in the activation lip (step 2). Phosphorylation causes the lip to move out of the kinase catalytic site, thus allowing ATP or a protein substrate to bind. The activated kinase then phosphorylates other tyrosine residues in the receptor's cytosolic domain (step 3). The resulting phosphotyrosines function as docking sites for various signal-transduction proteins (see Figure 14-6).

Once they are bound to an activated receptor, some signal-transduction proteins are phosphorylated by the receptor's intrinsic or associated kinase to achieve their active form. Binding of other signal-transduction proteins, present in the cytosol in unstimulated cells, positions them near their substrates localized in the plasma membrane. Both mechanisms can trigger downstream signaling. Several cytokine receptors (e.g., the IL-4 receptor) and RTKs (e.g., the insulin receptor)

▲ FIGURE 14-6 Recruitment of signal-transduction proteins to the cell membrane by binding to phosphotyrosine residues in activated receptors. Cytosolic proteins with SH2 (purple) or PTB (maroon) domains can bind to specific phosphotyrosine residues in activated RTKs (shown here) or cytokine receptors. In some cases, these signal-transduction proteins then are phosphorylated by the receptor's intrinsic or associated protein tyrosine kinase, enhancing their activity. Certain RTKs and cytokine receptors utilize multidocking proteins such as IRS-1 to increase the number of signaling proteins that are recruited and activated. Subsequent phosphorylation of the IRS-1 by receptor kinase activity creates additional docking sites for SH2-containing signaling proteins.

bind IRS1 or other multidocking proteins via a PTB domain in the docking protein (Figure 14-6).The activated receptor then phosphorylates the bound docking protein, forming many phosphotyrosines that in turn serve as docking sites for SH2-containing signaling proteins. Some of these proteins in turn may also be phosphorylated by the activated receptor.

Cytokines Influence Development of Many Cell Types

The cytokines form a family of relatively small, secreted proteins (generally containing about 160 amino acids) that control many aspects of growth and differentiation of specific types of cells. During pregnancy prolactin, for example, induces epithelial cells lining the immature ductules of the mammary gland to differentiate into the acinar cells that produce milk proteins and secrete them into the ducts. Another cytokine, interleukin 2 (IL-2), is essential for proliferation and functioning of the T cells of the immune system; its close relative IL-4 is essential for formation of functional antibody-producing B cells. Some cytokines, such as interferon a, are produced and secreted by many types of cells fol-

Hematopoietic stem cell

Epo receptors

Hematopoietic stem cell

Epo receptors

Erythroid progenitor (CFU-E)

Progenitors of other types of blood cells

Erythroid progenitor (CFU-E)

No Epo

Apoptosis (cell death)

Apoptosis (cell death)

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