Cytokine receptor signaling
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Cytokines are growth factors that specifically act to orchestrate the development of hemopoietic cells and the immune response
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X-SCID: INTERLEUKIN COMMON γ-CHAIN DEFICIENCY |
X-linked severe combined immunodeficiency (X-SCID) is a disorder causing very severe immunodeficiency. It is characterized by profoundly defective cellular and humoral immunity resulting in greatly increased susceptibility to infection, and is uniformly fatal by the time the patient is 1-2 years of age unless treated by bone-marrow transplantation. X-SCID males typically have profoundly defective cell-mediated and humoral immunity, with low numbers of T cells, or none at all, but normal numbers of B cells. |
Comment. The gene responsible for X-SCID was initially reported to code for the γ-chain of the IL-2 receptor. The extracellular domain of this γ-chain has been implicated in the high-affinity binding of IL-2 to its receptor and its intracellular domain associates with the signal transducer, JAK3, leading to gene induction, and cell growth and proliferation. However, the recent finding that the γ-chain is shared with the receptors for IL-4, IL-7, IL-9, IL-13, and IL-15 suggests that the severe immunodeficiency in X-SCID must be due to the patient's inability to respond to a number of or all these cytokines. (See also Chapter 36.) |
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Mitogen-activated protein kinase (MAPK) signaling cascades |
The MAPK cascade was originally elucidated by genetic studies in yeast, but the pathway has proved to be evolutionarily very highly conserved from yeast to mammals, allowing the mammalian elements to be identified by homology cloning. It has emerged in recent years that MAPKs are key components of an interacting network of sequential protein kinase cascades (MAPK cassettes) that serve to link early receptor-transduced signals with growth and differentiation-related transcriptional events in the nucleus. 'MAPK' is the generic name for a superfamily of signal transducing kinases that, to date, encompasses three major subfamilies, termed the extracellular regulated kinase (ERK; e.g. p44ERK1 and p42ERK2), stress activated protein kinase (SAPK) or Jun N-terminal kinase (JNK), and p38-reactivating kinase (p38RK) MAPK cassettes. These MAPK cassettes can phosphorylate transcription factors implicated in immediate early gene induction, such as AP-1 (Jun and Fos), ELK-1, and SAP1. Furthermore, whereas activation of the SAPKs and p38RKs can selectively induce apoptosis, under certain conditions, ERK1 and ERK2 generally act to promote cell survival and proliferation. |
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However, they can also have multiple effects on non-hemopoietic cell types (see Chapter 36). In common with growth
factors, they mediate their effects via specific cell-surface receptors; although there are several major classes of receptors, most cytokine receptors belong to the receptor superfamily called the hemopoietic receptors. These receptors are transmembrane glycoprotein receptors characterized by their conserved extracellular domains, which contain characteristic cysteine pairs and a pentapeptide WSXWS (tryptophan-serine-any-tryptophan-serine) motif. The receptors have no intrinsic catalytic activity, and many are multisubunit receptors, although not all of the chains necessarily belong to this receptor superfamily. These multisubunit receptors are generally characterized by a unique ligand-binding subunit that confers specificity, and a common signal transducer subunit that is often shared by several related cytokines and is the basis of the subdivison of the receptors into a number of distinct subfamilies. The sharing of common signal transducer subunits serves to explain the severe immunodeficiencies that result from naturally arising defects in these receptors.
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Ataxia telangiectasia is a rare autosomal recessive disease caused by mutations in the ataxia telangiectasia-mutated (ATM) gene. Symptoms and signs include an unsteady gait, telangiectasia, skin pigmentation, infertility, immune deficiencies, and an increased incidence of cancer, especially lymphoreticular tumors. |
Comment. ATM belongs to a protein kinase family that regulates the induction of DNA damage responses in reaction to ionizing radiation, anticancer treatment, or programmed DNA breaks during meiosis. Patients with ataxia telangiectasia show a large increase in cancer susceptibility and increased sensitivity to ionizing radiation. Ataxia telangiectasia cells show chromosomal instability, hypersensitivity to reagents that induce DNA-strand breaks, and defects in the G1/G2-phases, and altered regulation of the expression of p53 and p21 WAF1. ATM protein is constitutively expressed during the cell cycle and has been assigned a checkpoint function in monitoring DNA damage and determining whether p53-mediated growth arrest and DNA repair or p53-dependent apoptosis occurs in response to severe DNA damage. In ataxia telangiectasia, cells with mutated ATM fail to adequately activate p53, and hence to induce growth arrest or apoptosis in response to ionizing radiation. Moreover, when p53 is also mutated, the cell cycle is deregulated and the risk of tumor formation is enhanced as a result of the accumulation of mutations. |
As stated above, the hemopoietic receptors express no intrinsic catalytic activity; however, after ligation, these receptors stimulate tyrosine kinase activity and most cytokines, in common with the classical growth factors, signal through PLC, PI-3-K, and Ras-MAPK pathways (Fig. 41.4). However, a family of cytosolic protein tyrosine kinases (PTKs) has a crucial role in hemopoietic receptor signaling;
these kinases, called Janus kinases (JAKs), couple hemopoietic receptors to a novel transduction pathway that provides a direct link between receptor activation and gene transcription. Like the Src kinases, the JAKs are cytosolic tyrosine kinases. They associate with the hemopoietic receptors at conserved regions near the transmembrane domain and are activated and phosphorylated after cytokine binding and oligomerization of hemopoietic receptors.
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The major breakthrough in identifying the role of these kinases was obtained when the downstream targets of JAKs were identified as transcription factors called signal transducers and activators of transcription (STATs). STATs are found in a monomeric latent form in the cytoplasm of unstimulated cells. Cytokine stimulation leads to JAK-mediated phosphorylation and dimerization of STATs. STATs translocate to the nucleus, where they bind specific DNA sequences in the promoters of target genes and thus directly modulate gene induction (see Fig. 41.4). Recently, growth factors such as epidermal growth factor (EGF) and PDGF have also been shown to activate JAK/STAT pathways; thus this novel signaling cascade may provide a universal mechanism by which growth factors mediate gene induction and cellular responses.
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Figure 41.4 Cytokine receptor recruitment of JAK, STAT, and other intracellular signaling pathways. Fos, Jun, Myc, NF-kB, NF-AT transcription factors; GAS, gamma activation sequence; PKC: protein kinase C. cPKC, nPKC, aPKC: classical, novel, and atypical forms of protein kinase C (PKC); PLC, phospholipidase C; DAG, diacylglycerol; PIP3, inositol-3,4,5-trisphosphate; IP3, inositol-1,4,5-trisphosphate; PTK, protein tyrosine kinase; JAK, janus kinase. |
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