signaling paradigm. It is believed that engagement of ligands to their respective receptors results in an increased local concentration of Jak proteins due to receptor aggregation and increased affinity of the receptors for Jak kinases. Subsequent cross-phosphorylation of the Jaks results in the activation of their kinase activity, such that they can phosphorylate tyrosine residues in the receptor chains. These
phosphotyrosine moieties provide the docking sites for the STAT proteins via their SH2-domains, leading to their tyrosine phosphorylation, dimerization, and nuclear translocation. Parallel signaling events, presumably involving extracellular signaling regulated kinase/stress activated protein kinase (ERK/SAPK) family members, are responsible for further phosphorylation of the serine residues in the carboxy-terminus of the STAT proteins (Figure 4.1), which are required for efficient transcriptional response. In the case of growth factor receptors, not the presence of Jak kinases, but rather the intrinsic tyrosine kinase activity of the receptors is required for the tyrosine phosphorylation of STAT proteins.
As is the case with other signaling pathways, much of our understanding of the diverse functions of Jak and STAT proteins in vivo has been revealed through the generation of knockout mice . As anticipated, STAT1-deficient mice display dramatically increased sensitivity toward viral and microbial pathogens, presumably due to their inability to respond to interferons [17,18]. Disruption of the STAT3 gene results in early embryonic lethality, and only the use of conditional gene targeting revealed an essential role for STAT3 in T cell and macrophage function [19,20]. As predicted by the restricted activation of STAT4 by IL-12, Th1-cell development is severely impaired by the disruption of the STAT4 gene [21,22]. Consistent with the activation of STAT5 by prolactin, STAT5a-deficient mice fail to lactate; in contrast, the absence of STAT5b causes failure to respond to growth hormone . The role of STAT6 in IL-4 signaling was confirmed by the impairment of Th2 development and lack of IgE class switching. Jak1-deficient mice fail to nurse, display severely impaired lymphocyte development, and die perinatally [24,25]. The function of Jak2 in erythropoietin signaling is evidenced by embryonic lethality due to defective erythropoiesis in its absence . Of particular interest are results obtained from Jak3-deficient mice  because mutations in Jak3 have also been identified in humans. Jak3 interacts with the common cytokine receptor chain, a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, and mutation of which is responsible for X-linked severe combined immune-deficiency (X-SCID). Similarly, Jak3 deficiency in mice or mutations of Jak3 in humans causes SCID-like phenotypes .
Of equal importance to the activation of a signaling pathway is its spatially and temporally coordinated attenuation. Several independent mechanisms are responsible for the negative regulatory control over the Jak/STAT pathway. The two SH2-domain containing tyrosine phosphatases SHP-1 and SHP-2 are at least in part responsible for modulating the IFNa/p activation of the Jak/Stat pathway. SHP1 is associated with IFNAR1 and suppresses activation of the IFNa/p-induced Jak1 kinase . Contradicting reports exist on the role of SHP2 in IFNa/p-mediated STAT activation. Expression of dominant-negative SHP2 mutants inhibits IFNa-mediated gene induction , whereas the absence of SHP2 in gene-targeted animals leads to an enhanced interferon response .
The existence of a nuclear tyrosine phosphatase that inactivates STAT1 has been described by several labs [32,33]. This crucial attenuator of the interferon response was recently identified as the nuclear 45kDa isoform of T cell protein tyrosine phosphatase (TcPTP) .
The SH2-domain containing suppressor of cytokine signaling (SOCS, aka CIS) proteins have been identified as a family of seven cytokine-inducible inhibitors of the Jak/STAT pathway [35,36]. These proteins bind to either tyrosine phosphorylated receptors or activated Jak kinases and mediate their ubiquitin-dependent degradation , thereby inactivating these essential signaling components in a classical negative feedback loop. A ubiquitin-proteosomal degradation pathway for STAT1 has also been suggested as an attenuation mechanism of the IFN activated Jak/STAT pathway .
In contrast to the cytokine-inducible SOCS proteins, the constitutively expressed protein inhibitors of activated STATs (PIAS) proteins do not prevent the phosphorylation of STAT proteins, but exert their negative regulatory role by association with tyrosine phosphorylated STAT dimers and preventing them from binding DNA [39,40]. Recently, PIAS proteins have been shown to perform additional functions by acting as small ubiquitin-like modifiers (SUMO) E3-ligases for c-jun and p53 [41,42].
iii. cytokine activation of nfkb
Stress events such as infections or tissue damage cause the immune system to evoke an inflammatory response leading to a cascade of local and systemic counteracting effects. Components or products of infectious microorganisms, e.g., LPS, induce the expression of cytokines such as IL-1 and tumor necrosis factor (TNF). The binding of these proinflammatory cytokines to their cell surface receptors rapidly induces a genetic program to respond to cellular stress and to generate inflammatory mediators (e.g., chemokines, acute phase proteins, proteases, and prostaglandins). Chronic inflammation can result in extensive tissue destruction and disease, such as rheumatoid arthritis. Therefore, it is important that signaling molecules transducing IL-1 and TNF signals not only be triggered quickly but also signal transiently.
The transcription factor NFkB fulfills these characteristics. Although it is a key mediator in the inflammatory response, NFkB was first isolated in B cells as a factor necessary for immunoglobulin kappa light chain transcription. Later, NFkB was found to exist in most cell types . NFkB binding sites have been identified in a number of genes encoding cytokines and chemokines, adhesion molecules, acute phase proteins, anti-apoptotic genes, or transcription factors . Thus, NFkB was implicated in innate immunity as well as in the adaptive immune response. NFkB exists as a homo- or heterodimer of any of the five thus far isolated subunits—RelA (p65), RelB, c-Rel, p50, and p52. The p50 and p52 subunits are first generated as the longer p105 and p100 forms, respectively, which are then proteolytically processed into the shorter, active forms. All members contain a conserved Rel homology domain (RHD) within their N-terminus which contains the dimerization, IKB-binding and nuclear localization signal (NLS) regions. Additionally, RelA, RelB, and c-Rel contain a C-terminal transactivation domain that is absent in p50 and p52. Hence, p50 and p52 homodimers are transcriptionally repressive .
TNF and IL-1, and LPS itself, activate a pathway that results in the degradation of inhibitors of NFkB (IkB), freeing NFkB proteins from the cytosolic tether and exposing the NLS (see Figure 4.2). Similar to transcriptional induction via STAT proteins, the activation of NFkB does not require protein synthesis. Once in the nucleus, NFkB negatively regulates its own activity by inducing transcription of IkB, which enters the nucleus and chaperones NFkB molecules out through an active export pathway involving the IkB nuclear export sequence (NES) .
The IkB proteins bind to NFkB dimers and mask the NFkB NLS. The IkB family members (IKBa, IkBP, IKBe, IkBy, and Bcl-3) contain ankyrin repeats that bind the NFkB RHD, an N-terminal regulatory domain, and a C-terminal PEST motif for proteolytic degradation . Activators of the NFkB pathway trigger serine phosphorylation of IkB proteins (Ser32 and Ser36 on IKBa), which targets IkB for ubiquitin-mediated destruction by the 26S proteasome . Two closely related proteins with IkB kinase (IKK) activity were identified as IKKa and IKKp. Additionally, a putative scaffolding subunit was isolated and called IKKy (NFkB essential modulator = NEMO). IKKa and IKKp are 52% similar and both contain an N-terminal serine/threonine kinase domain, a leucine zipper, and a helix-loop-helix (HLH) motif . Upon stimulation by TNF and IL-1, the IKK subunits are phos-phorylated on serine residues. Substitution of alanines for these serines abrogated IKKp kinase activity and eliminated responses to TNFa and IL-10. However, mutations of the homologous serines within IKKa left TNF- and IL-1-induced NFkB activity intact, suggesting that IKKp is the main IKK kinase subunit through which
proinflammatory cytokines signal . The IKKa and IKKP knockout mice confirmed these earlier biochemical experiments, as IKKa-/- embryonic fibroblasts are normal in proinflammatory cytokine induced NFkB activation. In contrast, IKKP-/-mice, which die between embryonic day 12.5 and 14.5 similar to RelA-/- embryos from to severe fetal liver destruction, lack the ability to suppress TNF induced apoptosis via NFkB. Indeed, when RelA-/- or IKKP-/- mice are crossed to TNF receptor 1 or TNFa deficient mice, embryonic survival is rescued .
Analysis of the activation sites of the IKK kinases revealed that the mitogen activated protein kinase kinase kinase (MAPKKK) NFKB-Inducing kinase (NIK) activates the IKK complex and NFkB. NIK was originally isolated in a yeast two hybrid screen for TNF associated factor 2 (TRAF2) and was found to inhibit TNF-and IL-1-induced NFkB activation when expressed in a dominant negative form . The natural mouse mutant alymphoplasia (aly) were identified to have a single amino acid mutation (G855R) within the C-terminal TRAF interacting region of NIK. Interestingly, embryonic fibroblasts from NIK-/- mice are only defective in lympho-toxin-induced but not IL-1- or TNF-induced NFkB activation, suggesting that NIK plays a critical role in lymphotoxin signaling but not in the TNF or IL-1 pathways, despite the results of the earlier overexpression studies .
In addition to NIK, MAP/ERK Kinase Kinase 1 (MEKK1) can also phosphorylate IKKa in vitro . However, although MEKK1 activity is induced by TNF, MEKK1 is not as potent of a stimulator of IKK activity as NIK . Furthermore, inactivation of MEKK1 does not impair NFkB activation by TNF or IL-1 . Thus, additional kinases are likely to be involved in activating IKK in particular in vivo situations.
A number of adapter proteins link the IL-1 and TNF receptors to IKK activation and consequently NFkB activation. The TNFR1 is a death domain containing receptor. The death domains of TNFR1 interact with the death domain of FADD, initiating pro-apoptotic signals, but also bind the death domain of TRADD, thereby inducing the anti-apoptotic NFkB pathway. In turn, TRADD binds to TRAF2 . A dominant negative form of TRAF2 inhibits TNF-induced NFkB activation, nevertheless, TRAF2-/- fibroblasts have no defect in TNF-induced NFkB activation . However, TRAF2 recruits RIP1 (receptor interacting protein) to the TNFR complex, and RIP1-/- cells are deficient in NFkB activity .
The binding of IL-1 to the IL-1R also leads to the development of a signaling scaffold resulting in NFkB activation. First, the adapter protein MyD88 (myeloid differentiation factor 88) binds to the receptor. Interacting through its death domain, MyD88 binds the serine/threonine kinase IRAK (IL-1R associated kinase) , which in turn recruits TRAF6 to the complex. Both IRAK-/- and TRAF6-/- mice display defects in IL-1-induced NFkB activity. Additionally, the MAPKKK TAK1 (TGFp activated kinase) associates with TRAF6 in an IL-1-dependent manner, leading to activation of NFkB in a NIK dependent manner .
iv. additional signaling cascades in cytokine responses
In addition to the STATs, numerous other proteins undergo rapid tyrosine phosphorylation following exposure of cells to IFNa /p and other cytokines. Two members of the insulin receptor substrate (IRS) family of adapter proteins, IRS-1 and IRS-2, become tyrosine phosphorylated in response to a number of cytokines such as IFNa/p, IL-4, or IL-9, allowing for the SH2-domain mediated binding of the p85 regulatory subunit of PI-3 kinase [58,59]. The resulting activation of PI-3 kinase promotes the activity of proto-oncogene Akt (PKB) [60,61] and PKCd , which facilitates the survival and proliferation of cytokine-stimulated cells. Interestingly, PI-3 kinase activity might also be essential for certain IFNP-mediated transcriptional responses involving p65 , as well as the antiproliferative effects of IFNa/p , illustrating that the biological responses attributed to this signaling pathway can be altered due to modulation through other signaling events.
Two additional adapter proteins undergo rapid tyrosine phosphorylation after cytokine stimulation. The guanine nucleotide exchange factor and proto-oncogene Vav is activated by cytokines such as IL-3 or IL-6, and contribute to their mitogenic responses. In contrast, disrupted expression of the Vav abrogates the growth inhibitory effects of IFNa [65-67]. The proto-oncogene c-Cbl modulates cytokine signaling not only due to its function as an E3-ubiquitin ligase that promotes degradation of components of the cytokine signaling cascade, but also by providing docking sites for the src family kinase fyn  as well as the adapters CrkL and CrkII [69-71]. These SH2 and SH3 domain containing proteins link c-Cbl to Sos and C3G, a guanine nucleotide exchange factor for Rap-1 [72,73]. CrkL can associate with STAT5 and form a GAS-binding complex , and expression of CrkL and CrkII is essential for the antiproliferative effects of IFNa/p . Another signaling cascade regulated by cytokines is the MAP kinase pathway [76,77]. IFNa/p activates Raf-1 as well as B-Raf, two serine kinases ultimately responsible for the activation of p42MAP kinase, in a Jakl-kinase and STATl-dependent manner [78-80]. Likewise, it has also been reported that the p38 SAPK is activated by IFNa/p [81,82]. Ser 727 of Statl, which is conserved in Stat3 and Stat4, is positioned within a consensus phosphorylation site for proline-directed serine kinases such as MAP kinases . However, as other cytokine-activated kinases, such as PKCd  or CamKII , also have the ability to phosphorylate Ser727 of STAT1 in vitro, it remains unclear which kinase is ultimately responsible for the phosphorylation of STAT1 Ser727 in vivo.
In this chapter we have attempted to outline the events leading to cytokine mediated gene transcription by using that Jak/STAT and the NFkB pathways as two examples. It is important to remember that cytokine activation of gene transcription is not the result of a single, linear signaling cascade, but involves a complex network of interacting signal transduction pathways. Integration of numerous, often contradicting instructions received by the cell through a variety of cytokine and growth factor receptors, ultimately determines the qualitative and quantitative transcriptional response.
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