Evolution of the Class 2 cytokines and receptors, and discovery of new friends and relatives

Krause, Christopher D.; Pestka, Sidney

doi:10.1016/j.pharmthera.2004.12.002

Cited by 123 publications

(104 citation statements)

References 188 publications

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“…This was also the case for class 1 and class 2 cytokines and their receptors 90,91 . Given their physiological and physical interaction, it will be interesting to assess whether cytokine and TAM receptors may have co-evolved.…”

Section: Box 2 | Primordial Tam Receptors and Ligandsmentioning

confidence: 53%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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Section: Box 2 | Primordial Tam Receptors and Ligandsmentioning

confidence: 53%

Immunobiology of the TAM receptors

2008

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“…The IFNT/IFNW split occurred much more recently, only 36 million years ago, and coincided with the time the ruminant artiodactyls themselves first emerged. A recent comprehensive analysis of Type 1 IFN phylogeny (19) confirms the recent evolutionary origins of the IFNT and the inference that these genes will not be found outside the ruminant order and certainly not in either mouse or man (as has been occasionally and mistakenly reported). The initial event that gave rise to the IFNT was most probably a duplication event from an existing IFNW that provided the new tau gene with a reorganized promoter and a novel 3 / -end.…”

Section: Relationship Of Ifn-τ To Other Type 1 Ifnmentioning

confidence: 74%

Interferon-tau, a Type 1 interferon involved in maternal recognition of pregnancy

Roberts

2007

Cytokine & Growth Factor Reviews

108

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Interferon-τ is a major product of ovine and bovine conceptuses during the period before the trophoblast makes firm attachment to the uterine wall and begins to form a placenta. Its primary function is in preventing a return to ovarian cyclicity and hence ensuring the pregnancy continues, although it undoubtedly has other roles in ensuring receptivity of the maternal endometrium. Despite having properties similar to those of other Type 1, IFN-τ is not virally inducible and functions in a constitutive process unrelated to pathogenesis. The genes for IFN-τ (IFNT), which are confined to ruminant ungulate species, would appear to be the most recently evolved mammalian Type 1 gene family and are primarily under the transcriptional control of Ets2 and signal transduction pathways that target that transcription factor. The IFNT provide an illustration of how a gene control region can be commandeered and then refined to provide a radically changed pattern of expression.

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“…In addition, the prototypic complement-effector pathway, consisting of C3 and membrane-attack complex-perforin proteins, has also been identified in Cnidarians. The evolution of type I IFNs occurred at a much later time and type I IFNs are identified only in vertebrates (51). Knocking out type I IFN signaling by targeted deletion of type I IFNreceptor genes augments sensitivity of mice to even minute levels of most viral infections, indicating that type I IFN confers primary innate antiviral immunity (8).…”

Section: The Evolutionary Path To Innate Immunity: a Continuing Procementioning

confidence: 99%

Evolution of MDA-5/RIG-I-dependent innate immunity: Independent evolution by domain grafting

Sarkar

DeSalle

Fisher

2008

Proc. Natl. Acad. Sci. U.S.A.

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Interferons (IFNs) comprise a family of secreted proteins (cytokines) produced by cells following virus infection and create an antiviral state in neighboring cells (1-6). The relationship between IFN and viral infection is well documented and supported by studies employing neutralizing antibodies and IFN-receptor knockout mice, which document a direct role for IFN in mediating host defense against viruses (7,8). Moreover, IFNs are now recognized as multifunctional molecules that also provide defense against bacterial infection (especially intracellular parasites), induce antitumor activity (both direct and immune system-mediated), and stimulate or inhibit differentiation depending on cellular context (5, 9). In addition, type I IFNs also induce apoptosis of virus-infected cells and activate natural killer and T cells, thus activating the adaptive immune system as well (3).The expression of type I IFN is stringently regulated by the activation of pre-existing transcription factors, such as IFN regulatory factor 3 (IRF-3), NF-B, and ATF-2-c-Jun [supporting information (SI) Fig. S1] (10-12). These transcription factors are activated and, therefore, type I IFN is induced by bacterial components, such as lipopolysaccharide, and CpG DNA in leukocytes, such as macrophages and dendritic cells, as well as by viral infection (13,14). Targeted-gene-disruption studies indicate that Toll-like receptors (TLRs) recognize pathogenassociated molecular patterns. TLR3, TLR4, mouse TLR7 (human TLR8), and TLR9 function as signaling receptors for extracellular double-stranded RNA (dsRNA), lipopolysaccharide, viral single-stranded RNA, and CpG DNA, respectively (15-18). The interaction of these pathogen-associated molecular patterns with the extracellular leucine-rich repeat of the TLR facilitates the recruitment of adaptor molecules to the cytoplasmic Toll-IL-1 receptor domain of the TLR (19). The adaptors MyD88, IL-1 receptor associated kinase (IRAK), and TRAF6 are recruited by many TLRs and activate signaling cascades. For TLR7 and TLR9, type I IFN is induced by this MyD88-dependent pathway (19). TLR4 and TLR3 activate an additional signaling pathway called the MyD88-independent pathway, which recruits another adaptor molecule, Trif, and activates a second set of genes, including those of type I IFN, through activation of IRF-3 (20, 21). However, for most cell types, it has been postulated that the replication of viruses results in an accumulation of intracellular dsRNA, which triggers host response mechanisms that include expression of type I IFN (22). This signaling pathway is apparently distinct from that mediated by TLR3 and constitutes a major pathway activated by viral infection.Recent studies identified two proteins, melanoma differentiation associated gene-5 (MDA-5) and retinoic acid inducible gene I (RIG-I), as intracellular sensors of dsRNA responsible for induction of type I IFN (23, 24). Analysis of mda-5 or RIG-I knockout mice demonstrates that this TLR-independent pathway is central for innate immunity against viral ...

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Evolution of the Class 2 cytokines and receptors, and discovery of new friends and relatives

Cited by 123 publications

References 188 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Interferon-tau, a Type 1 interferon involved in maternal recognition of pregnancy

Evolution of MDA-5/RIG-I-dependent innate immunity: Independent evolution by domain grafting

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