The Jakstat Signaling Pathway

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The proliferation and differentiation of peripheral blood progenitor cell (PBPC) populations to form myeloid, erythroid, and lymphoid populations is controlled by the actions of cytokines. Most cytokine receptors consist of a cytokine-specific binding subunit as well as a signal-transducing subunit, but, unlike many growth factor receptors, such as those for macrophage colony-stimulating factor (M-CSF) and epidermal growth factor (EGF), they generally lack intrinsic kinase activity, rather, cytokine binding to receptor subunits results in homo- or heterodimerization bringing signaling proteins associated with the cytoplasmic domains of the receptors in close contact with each other. The biologic actions of the hematopoietic family of

From: Cancer Drug Discovery and Development Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics Edited by: G. Morstyn, M. A. Foote, and G. J. Lieschke © Humana Press Inc., Totowa, NJ

cytokines are orchestrated by a number of signaling pathways, one of the most important being the Janus kinase-signal transducers and activators of transcription (Jak-Stat) signaling pathway.

The proximity of cytoplasmic tails of receptor subunits after cytokine binding allows the constitutively associated Jaks to cross-phosphorylate each other on tyrosine, further activating their kinase activity and resulting in additional tyrosine phosphorylation of the receptor and other signaling molecules. This action produces docking sites on the receptor for signaling molecules, such as Stat proteins that are subsequently also phosphory-lated by Jak. Activated phosphorylated Stat proteins then dissociate from the receptor and homo- or heterodimerize in the cytoplasm before translocating to the nucleus by an ill-defined mechanism to activate transcription (Fig. 1). Other signaling pathways are activated in response to cytokine activation including Src and mitogen-activated protein (MAP) kinases that contribute to proliferation, differentiation, functional activation, and survival of cells. It is envisaged that the cell-specific actions of cytokines could be determined at multiple levels, including expression levels of the receptor and signaling components, presence of negative regulators, and crosstalk between cytokines.

Cytokine receptors are classified according to common structural motifs and can be broadly grouped into five categories: hematopoietin/interferon (IFN; class I/class II) family, receptor tyrosine or serine/threonine kinase family, tumor necrosis factor (TNF)/nerve growth factor (NGF) family, toll-like receptors, and seven-transmembrane receptor family.

This chapter focuses predominantly on the hematopoietin/IFN and tyrosine kinase receptor families. The hematopoietin/IFN receptors contain several conserved features including hematopoietin and IFN receptor domains, as well as fibronectin type III and immunoglobulin-like domains. The hematopoietin and IFN receptor domains contain conserved cysteine and tryptophan residues in their N-terminal region and, in the case of hematopoietin receptors, a conserved tryptophan-serine-X-tryptophan-ser-ine (W-S-X-W-S) sequence in the C-terminus of the extracellular domain (where "X" refers to any amino acid residue). This motif is absent in class II receptors. In contrast, the receptor tyrosine kinase family, which includes receptors for M-CSF, platelet-derived growth factor (PDGF), and stem cell factor (SCF), contains immunoglobulin-like extracellular domains, and intracellular tyrosine kinase domains that distinguish them from other hematopoietic growth factor and IFN receptor family members.

Cytokine families that share similar biologic functions often share common receptor subunits and signaling pathways (Table 1). The gp130 signal-transducing, common receptor P-chain is shared by inflammatory cytokines such as interleukin (IL)-6 and IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1). A unique ligand-binding a-chain provides specificity for each cytokine. The receptors for the hematopoietic family of cytokines, which include IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF), feature a unique ligand-binding a-chain but share a common Pc signal-transducing subunit. The IL-2 family of immunomodulatory cytokines features a common IL-2y signal-transducing subunit (yC), shared by IL-2, IL-4, IL-7, IL-9, and IL-15. The P-subunit is an additional signal-transducing subunit for IL-2 and IL-15, and the a-subunit is a unique ligand-binding chain. The IFN family of cytokines signals through separate ligand-binding and signal-transducing chains. IFN-a signals through the IFN-a receptor (IFN-aR). The receptor for IFN-y comprises both the

Interferon Family

Fig. 1. The Jak-Stat signaling pathway is activated in response to cytokine stimulation. Binding of the ligand to the receptor induces dimerization of the receptor, allowing the constitutively associated Jaks to crossphosphorylate on tyrosine residues, thereby enhancing their kinase activity. Activated Jaks phos-phorylate the receptor subunits on tyrosine residues, producing binding sites for Stat proteins, which are themselves phosphorylated by Jak. Phosphorylated Stat proteins dissociate from the receptor and homo-or heterodimerize before translocating to the nucleus, where they induce transcription of target genes. One family of Stat-inducible genes are the suppressors of cytokine signaling (SOCS) genes, which form part of a classical negative regulatory feedback mechanism to inhibit cytokine signaling by interfering with Jak kinase activity or by binding to the receptor and thereby preventing access of Stat molecules to phosphorylated tyrosine residues. In addition, SOCS proteins target binding partners for proteasomal degradation via the SOCS box domain. The protein inhibitor of activated Stat (PIAS) proteins can also interact with and inhibit the actions of activated Stat molecules.

Fig. 1. The Jak-Stat signaling pathway is activated in response to cytokine stimulation. Binding of the ligand to the receptor induces dimerization of the receptor, allowing the constitutively associated Jaks to crossphosphorylate on tyrosine residues, thereby enhancing their kinase activity. Activated Jaks phos-phorylate the receptor subunits on tyrosine residues, producing binding sites for Stat proteins, which are themselves phosphorylated by Jak. Phosphorylated Stat proteins dissociate from the receptor and homo-or heterodimerize before translocating to the nucleus, where they induce transcription of target genes. One family of Stat-inducible genes are the suppressors of cytokine signaling (SOCS) genes, which form part of a classical negative regulatory feedback mechanism to inhibit cytokine signaling by interfering with Jak kinase activity or by binding to the receptor and thereby preventing access of Stat molecules to phosphorylated tyrosine residues. In addition, SOCS proteins target binding partners for proteasomal degradation via the SOCS box domain. The protein inhibitor of activated Stat (PIAS) proteins can also interact with and inhibit the actions of activated Stat molecules.

Table 1

Hematopoietin (Class I) and Interferon (Class II) Family Receptors

Table 1

Hematopoietin (Class I) and Interferon (Class II) Family Receptors

Ligands

Jak

STAT

gp 130 family

IL-6

Jak1, Jak2, Tyk2

Stat3, Stat1

IL-11

Jak1, Jak2, Tyk2

Stat3, Stat1

LIF (shares LIFR chain)

Jak1, Jak2, Tyk2

Stat3, Stat1

OSM (shares LIFR chain)

Jak1, Jak2, Tyk2

Stat3, Stat1

Leptin (gp130-related receptor)

Jak2

Stat4

CNTF (also shares LIFR chain)

Jak1, Jak2, Tyk2

Stat3, Stat1

CT-1 (also shares LIFR chain)

Jak1, Jak2, Tyk2

Stat3

IL-12 (gp130-related receptor)

Tyk2, Jak2

Stat4, Stat1, Stat3

IL-23

Stat4

NNT-1/BSF-3 (also shares LIF

Jak1, Jak2

Stat3, Stat1

and CNTF chains)

IFN family

IFN-a/ß

Tyk2, Jak1

Stat1, Stat2, Stat3, Stat4,

Stat5

IFN-y

Jak1, Jak2

Stat1, Stat5

IL-10

Tyk2, Jak1

Stat3, Stat1, Stat5

IL-19

IL-20

Stat3

IL-22

Jak1, Tyk2

Stat1, Stat3, Stat5

IL-3 (gp 140) family

GM-CSF

Jak2

Stat5

IL-3

Jak2

Stat3, Stat5

IL-5

Jak2

Stat1, Stat3, Stat5

IL-2 (yC) family

IL-2 (also shares common ß-chain)

Jak1, Jak2, Jak3

Stat5, Stat3

IL-4

Jak1, Jak3

Stat6

IL-7

Jak1, Jak3

Stat5, Stat3, Stat1

IL-9

Jak1, Jak3

Stat5, Stat3

IL-15 (also shares common ß-chain)

Jak1, Jak3

Stat5, Stat3

IL-21

Jak1, Jak3

Stat5, Stat3, Stat1

IL-13 (shares IL-4Ra chain but not yC)

Jak1, Jak2, Tyk2

Stat3, Stat6

IL-14 (shares a-chain)

Single-chain family

EPO

Jak2

Stat5

G-CSF

Jak1, Jak2, Tyk2

Stat1, Stat3, Stat5

GH

Jak2

Stat5

PRL

Jak1, Jak2, Jak3

Stat1, Stat3, Stat5

TPO

Jak2, Tyk2

Stat3, Stat5

Receptor tyrosine kinases

M-CSF

Tyk2, Jak1

Stat1, Stat3, Stat5

EGF

Jak1, Jak2

Stat1, Stat3, Stat5

PDGF

Jak1, Jak2

Stat1, Stat3

HGF

Stat1, Stat3

SCF

Jak2

Stat1, Stat3, Stat5

(table continues)

Table 1

(continued)

Ligands

Jak

STAT

Unknown

IL-17

Jak1, Jak2, Jak3

Statl, Stat2, Stat3, Stat4

IL-18

Stat3

TSH

Jak1, Jak2

Stat3

Insulin

Statl, Stat3, Stat5

Pseudo-Kinase Domain

Kinase Domain

Fig. 2. Jaks are composed of multiple Jak homology (JH) domains. The JH1 domain has tyrosine kinase activity. The JH2 pseudokinase domain is thought to regulate kinase activity, whereas the JH6 and JH7 domains may interact with the receptor.

IFN-yRl and IFN-yR2 subunits. Similarly, the receptor for IL-10 comprises both the IL-10R1 and IL-10R2 subunits.

The families of receptors for erythropoietin (EPO), growth hormone (GH), throm-bopoietin (TPO), and prolactin (PRL) consist of homodimers of a single-receptor chain specific for each cytokine. Unlike the aforementioned cytokine receptors that lack intrinsic tyrosine kinase activity, the receptor tyrosine and serine/threonine kinases, such as receptors for EGF, M-CSF, and PDGF, can phosphorylate and activate signaling cascade components independently of Jak.

The receptor chains and receptor-associated Jaks are brought in close contact upon cytokine binding, allowing trans-phosphorylation on tyrosine. The Jaks contain four family members—Jak1, Jak2, Jak3, and Tyk2. They appear to be ubiquitously expressed, except for Jak3, in which expression is restricted to hematopoietic cells. Structurally, the Jaks are characterized by seven Jak homology (JH) domains (Fig. 2). The C-terminal tyrosine kinase JH1 and pseudokinase JH2 domains constitute a large portion of these 120-130-kDa proteins. The N-terminal JH3-JH7 domains are smaller, and their function is unclear. Studies suggest that the JH6-JH7 domains may be important for interaction with the receptor, whereas the JH2 pseudokinase domain (which lacks any detectable kinase activity) may be important for regulation of kinase activity.

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