Evolution of Signaling Clifford Liongue, Robert Sertori and Alister C. Ward J Immunol 2016; 197:11-18; ; This information is current as doi: 10.4049/jimmunol.1600372 of September 24, 2021. http://www.jimmunol.org/content/197/1/11 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/06/13/197.1.11.DCSuppl Material emental References This article cites 105 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/197/1/11.full#ref-list-1 http://www.jimmunol.org/

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology

Evolution of Signaling Clifford Liongue, Robert Sertori, and Alister C. Ward represent essential mediators of cell–cell com- transcription factors (4–6), which represents one of the seven munication with particularly important roles within the major signaling pathways controlling bilaterian development . These secreted factors are produced in (7). Once tyrosine phosphorylated, the STATs dimerize and response to developmental and/or environmental cues translocate to the nucleus where they influence transcrip- and act via cognate cytokine receptors on target cells, tion to mediate key phenotypic changes in the cell (3). stimulating specific intracellular signaling pathways to Signaling is subsequently extinguished in a number of ways, facilitate appropriate cellular responses. This review de- including by the action of tyrosine phosphatases, such as scribes the evolution of cytokine receptor signaling, fo- the Src homology 2 (SH2) domain–containing ty- rosine phosphatases (SHPs), as well as induction of sup-

cusingontheclassIandclassIIreceptorfamiliesand Downloaded from the downstream JAK–STAT pathway along with its pressor of cytokine signaling (SOCS) that inhibit key negative regulators. Individual components gener- CytoR signaling by several mechanisms, providing a clas- sical negative-feedback loop (5, 8, 9). ated over a long evolutionary time frame coalesced to The archetypal CytoR–JAK–STAT signaling module is form an archetypal signaling pathway in bilateria that typified by that found in extant protostomes, such as insects, was expanded extensively during early vertebrate evolu- which consists of one CytoR that initiates signaling via a sole tion to establish a substantial “core” signaling network, JAK that activates a single STAT to mediate its effects, with http://www.jimmunol.org/ which has subsequently undergone limited diversifica- one SHP and several SOCS proteins contributing to the neg- tion within discrete lineages. The evolution of cytokine ative regulation of this signaling pathway (10). The various receptor signaling parallels that of the immune system, CytoR–JAK–STAT signaling components expanded signifi- particularly the emergence of adaptive immunity, which cantly during vertebrate evolution, such that mammals possess has likely been a major evolutionary driver. The Journal .50 CytoR molecules serviced by four JAKs and seven STATs, of Immunology, 2016, 197: 11–18. along with two SHP and eight SOCS proteins (4). This review summarizes the evolution of the class I and class II CytoR signaling pathway, exploring the origins of individual compo- by guest on September 24, 2021 he generation of mechanisms that enable efficient cell– nents and their subsequent expansion and diversification to cell communication has been critical in the evolution become a cornerstone of communication between cells, par- T of the complex cell systems that characterize multi- ticularly those of the immune system, the evolution of which cellular organisms, including immunity. One such mecha- CytoRs have likely shaped in profound ways. nism is mediated by an array of secreted factors collectively termed cytokines (Cytos). These small polypeptides are pro- Emergence of the pathway duced in response to a variety of stimuli and act via specific Each of the core components of the CytoR signaling paradigm Cyto receptors (CytoRs) expressed on the surface of target consists of modular protein domains, many of which have a cells (1). The so-called class I and class II families of CytoRs long evolutionary history (Fig. 1). The initial steps in the mediate key aspects of immunity in addition to other devel- evolution of CytoR signaling involved the generation of the opment and homeostatic roles (2). individual components of the pathway and their subsequent The class I and class II receptors lack intracellular kinase consolidation into a functional signaling system. The compo- activity and instead depend on associated tyrosine kinases, nents arose largely by accretion of pre-existing domains across a particularly members of the JAK family (3, 4). Ligand binding broad evolutionary time frame. However, the generation of all leads to conformational changes in the CytoR complex that components of the canonical CytoR–JAK–STAT module and activate associated JAKs to initiate various downstream sig- their coalescence into a functional pathway only occurred in naling pathways, importantly including the STAT family of bilateria (Fig. 1) (11).

School of Medicine, Deakin University, Waurn Ponds, Victoria 3216, Australia; and The online version of this article contains supplemental material. Centre for Molecular and Medical Research, Deakin University, Waurn Ponds, Victoria Abbreviations used in this article: CHD, CytoR homology domain; CRLF, CytoR-like 3216, Australia factor; Cyto, cytokine; CytoR, Cyto receptor; FBN, fibronectin; FERM, four-point-one, ORCIDs: 0000-0002-1646-4905 (C.L.); 0000-0001-7945-7975 (A.C.W.). ezrin, radixin, moesin; PTP, protein tyrosine phosphatase; SH2, Src homology 2; SHP, Src homology 2 domain–containing protein tyrosine phosphatase; SOCS, sup- Received for publication March 3, 2016. Accepted for publication April 10, 2016. pressor of cytokine signaling; TF, ; TK, ; WGD, whole- This work was supported by a Postgraduate Research Award (to R.S.) and an Alfred genome duplication. Deakin Postdoctoral Research Fellowship (to C.L.) from Deakin University. Ó Address correspondence and reprint requests to Prof. Alister C. Ward, School of Med- Copyright 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 icine, Deakin University, Pigdons Road, Waurn Ponds, VIC 3216, Australia. E-mail address: [email protected]

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600372 12 BRIEF REVIEWS: CYTOKINE RECEPTOR EVOLUTION

Generating the components. Individual components of the cy- called “long” chain conformation most similar to vertebrate tokine signaling pathway were assembled largely from pre- and IL-6 (13, 14). existing domains that were modified for purpose. CytoRs. Class I and class II receptors are cell surface protein Cytokines. The ligands that activate class I and class II receptors complexes that consist of one to four receptor chains, at least one are small polypeptides ∼5–25 kDa, which derive from a four of which can transmit an intracellular signal to mediate the effects helix–bundle structure that has been used in diverse proteins of the cytokine. These receptor chains possess an extracellular across evolution, from cytochromes to ferritin (12). The first CytoR homology domain (CHD) consisting of two fibronectin definitive representatives are present in extant bilateria, charac- (FBN) type III folds with a connecting sequence associated terized by the fruit-fly Unpaired proteins, which possess a so- with cytokine binding. They are divided into two families Downloaded from http://www.jimmunol.org/ by guest on September 24, 2021

FIGURE 1. Coalescence of the CytoR signaling pathway. Schematic representation of the evolutionary history of individual CytoR signaling components is depicted in the outer hexagonal segments: Cyto (gray), CytoR (blue), JAK (green), STAT (brown), SHP (purple), SOCS ( orange), including a simplified tree of the key organismal groups considered. The domain architecture of each component within these groups is depicted, showing the accretion (purple arrows) and modification or de novo generation of protein domains into the archetypal topology (outlined). This coalesced into a functional CytoR signaling pathway in bilateria (central circle), in which Cyto binding to the CytoR causes conformational changes that initiate JAK activation and CytoR phosphorylation, creating docking sites for STAT. These are phosphorylated by JAK (blue arrow) and translocate to the nucleus (yellow arrow) to initiate transcription of target (green arrow) to mediate an appropriate response, as well as induce SOCS proteins, which negatively regulates this pathway (dotted red line), along with SHP proteins that act via tyrosine dephosphorylation (solid red line). FBN, FBN type III; 4HB, four helix bundle; TAD, transactivation domain. The Journal of Immunology 13 based on structural differences within the CHD: class I SOCSs. SOCS proteins consist of a variable N-terminal receptor chains possess two pairs of disulfide-linked cysteines domain, followed by SH2 and SOCS box domains. Proteins within the first FBN fold and a highly conserved WSXWS containing SOCS box domains were identified in extant motif toward the C terminus of the second FBN fold (15–17), choanoflagellates (12), but only porifera possess proteins in whereas class II receptor chains have one cysteine pair located whichaSOCSboxisassociatedwithanSH2domainand in each FBN fold of their CHD (18). The CytoR chains can small N-terminal sequence to form an archetypal SOCS also possess additional domains, including extracellular Ig-like protein (12). Interestingly, this pathway component was and FBN-like regions, as well as transmembrane and in- subsequently replicated to yield three distinct lineages in tracellular sequences essential for (15, bilateria (37), which are differentially used in the CytoR 19). Ig and FBN domains were generated independently early signaling paradigm (38, 39). in evolution and have been widely used as components of many Assembling the components. Exactly how the archetypal CytoR– protein families (12). However, the hallmark CHD appears to JAK–STAT signaling pathway arose is a matter of specula- have arisen later, being found in extant placozoa in a protein tion. We recently argued that assembly of the core CytoR– displaying homology to vertebrate CytoR-like factor (CRLF)3, JAK–STAT module is consistent with the “retrograde” model which consists predominantly of a class I–related CHD (11). of pathway evolution, with STATs, then JAKs, and then Only in bilaterians did a CHD become associated with Ig-like, CytoRs becoming associated into a functional pathway as a FBN-like, and transmembrane domains, as well as intracellular result of a series of relatively minor changes, whereas pre- sequences, to form an archetypal receptor that is structurally existing negative regulators were able to be recruited from Downloaded from related to the vertebrate class I receptor chain gp130 (GP130) other pathways in a “patchwork” manner (11). As a corollary, it and exemplified by the fruit fly Dome protein (20) and the is almost certain that many, if not all, of the individual related, but signaling-incompetent, ET/Latran protein that components functioned in alternative roles prior to their acts as a negative regulator (21). recruitment into the CytoR–JAK–STAT pathway. Evidence JAKs. JAKs possess a unique four-domain architecture consisting supporting this assertion can be inferred from the involvement of of an N-terminal four-point-one, ezrin, radixin, moesin (FERM) several components in noncanonical signaling in extant species. http://www.jimmunol.org/ domain followed by a variant SH2 domain that collectively For example, several roles were identified for STAT proteins that mediate interactions with CytoR intracellular domains (6, 22). are independent of CytoRs and JAKs. These include the control Proximal to this is a so-called “pseudokinase” domain with of cell growth, differentiation, chemotaxis and immune responses homology to tyrosine kinase (TK) domains but no catalytic in slime mold downstream of G-protein–coupled receptors activity, which plays a regulatory role. Finally, at the C terminus (29), and the regulation of metabolic functions in vertebrates isaclassicalTKdomain(23,24).FERM,SH2,andTKdo- by unphosphorylated STATs (40, 41). Similarly, several SOCS mains arose separately in early eukaryotes but only became members are principally involved in the regulation of growth combined later. A JAK-like protein was identified in extant factor receptors and other pathways (39). by guest on September 24, 2021 porifera; it consists of a FERM, SH2, and single TK domain Functions of the archetypal CytoR pathway. The archetypal (25), which shows high conservation with JAK TK domains CytoR–JAK–STAT signaling pathway has a diverse range of (11). However, incorporation of the additional pseudokinase functions, as detailed most extensively in fruit fly. In this domain to form a canonical JAK appears only in bilateria, organism it is involved in embryonic segmentation (42), eye as observed, for example, in fruit fly Hopscotch (26), which development (43), stem cell proliferation in the testes (44) is likely due to duplication and subsequent modification of and intestine (45), as well as controlling growth and meta- sequences encoding the adjacent TK domain (11). bolism (46). Importantly, it also functions in innate immunity, STATs. STAT proteins consist of conserved central coiled-coil, with a role in the maintenance of multilineage progenitors in DNA binding, and SH2 domains, as well as the more variable normal hematopoiesis, immune cell proliferation in response to N-terminal and C-terminal domains (23). This protein family immune challenge, the production of antimicrobial has ancient roots, with the most divergent being the plant GRAS and intestinal epithelium repair in response to gut bacteria, as proteins, which possess an SH2-like domain and a putative well as antiviral responses (45, 47) that have been confirmed in DNA-binding domain (27), whereas present-day slime mold other insects, including mosquito (48). possess a STAT-like protein that includes a coiled-coil domain Expansion of the pathway involved in transcriptional regulation added via domain accre- The consolidation of an archetypal CytoR–JAK–STAT path- tion (28, 29). The N-terminal and C-terminal transactivation way over a large evolutionary time frame was followed by domains formed later (30–33), with a definitive archetypal a relatively rapid multiplication of pathway components STAT clearly identifiable in bilateria (11, 34), as exempli- (Fig. 2). As a result, the majority of the CytoR–JAK–STAT fied in the present-day fruit fly Marelle protein (34), which signaling components were already in place at the time of di- is most homologous to higher vertebrate STAT5 and STAT6. vergence of bony fish (including mammals) and cartilaginous SHPs. SHP proteins consist of tandem SH2 domains, followed fish (including sharks) around 420 million years ago, repre- by a protein tyrosine phosphatase (PTP) domain, both of senting the “core” CytoR signaling network. Local duplica- which predate holozoa. However, a SHP-like protein with a tions of individual components appear to have contributed to single SH2 domain linked to a PTP domain is observed in this process, but the two rounds of whole-genome duplication present-day choanoflagellates (35), suggesting that this topology (WGD) that occurred during early vertebrate evolution (49) evolved in holozoa (10). The archetypal SHP topology was represent the major mediator of the expansion (20, 34, 37). generated in early metazoans, with the dual SH2–PTP Cyto/CytoRs. Early in chordate evolution, a precursor of the structure identified in extant porifera (36). class II receptors was generated, presumably via duplication 14 BRIEF REVIEWS: CYTOKINE RECEPTOR EVOLUTION Downloaded from

FIGURE 2. Expansion of the CytoR signaling pathway. Schematic representation of the relative numbers of each CytoR component in key extant species (fruit fly, http://www.jimmunol.org/ sea squirt, elephant shark, zebrafish, and human) and the deduced core components present in the indicated ancestors (dashed black rectangle). These are shown numerically within the respective hexagonal segments: class I CytoR chains (blue), class II CytoR chains (light blue), JAKs (green), STATs (brown), SHPs (purple), and SOCSs (light orange). CHD-containing CRLF3 and TF are not included in these numbers because they are not involved in archetypal CytoR signaling. Arrows represent presumed evolutionary relationships, with WGD events indicated (red arrows) along with organisms with innate (yellow box) and adaptive (blue box) immune systems. The information in this figure was derived from the “consensus” of a number of studies (20, 37, 51–53, 55–57, 59, 65, 74, 96, 100, 103–106) along with extensive analysis of the annotated elephant shark and spotted gar genomes. by guest on September 24, 2021 of the original class I–related CytoR and representing the IL-9?), one using the related IL-13Ra (IL-13R) complex, and archetypal IFNR involved in initiating and coordinating two using the common IL-3Rbc chain (IL-5R and an additional antiviral responses (50). These original class I and class II re- complex that is the likely precursor for IL-3R and GM-CSFR, ceptor chains further expanded via a combination of local du- termed IL-3/GMR), as well as the heterotrimeric precursor of plications and WGDs to generate a set of receptor chains IL-2R and IL-15R (termed IL-2/15R) (Fig. 3, Supplemental Fig. covering all major CytoR topologies by the divergence of bony 3). Other “core” CHD-containing molecules present include and cartilaginous fish (20, 37, 51–54). For class I receptor several that interact with cytokines extracellularly to form active chains, there are representatives for each of the five structural heterodimers (IL-12p40, IL-27Rb, CRLF1) or act as a so-called groups (55) and a single copy of the alternate sushi domain- “decoy” (IL-13Ra2). based receptor chain used in mammalian IL-2R and IL-15R. For Class II. Core receptors comprise single type I, type II, and type class II, it includes “short” and “long” chains belonging to the III IFNRs, as well as representatives for each of the IL-10R IFNR and IL-10R families. The cytokine ligands are notoriously family members (IL-10R, IL-20R, IL-22R, IL-26R) (Fig. 3, difficult to definitively identify, but the available data suggest Supplemental Fig. 4). They also include the CHD-containing that they largely coevolved in parallel (56, 57). IL-22 decoy (IL-22BP) and tissue factor (TF), the latter of Assuming conserved assembly of these receptor chains into which is not involved in cytokine signaling. functional CytoR complexes, a “core” set of CytoRs can be de- Other components. The bulk of the diversity of the other CytoR duced that covers all receptor topologies, which includes repre- signaling pathway components was also generated within the sentatives of the majority of class I and class II CytoRs (Fig. 3). same evolutionary period. Precursors of all four mammalian Class I. The core receptors include precursors for each of the JAKs (JAK1-3, TYK2) arose from the archetypal JAK sequence mammalian homodimeric group 1 receptors (EPOR, TPOR, via the sequential rounds of WGD (37, 58). In contrast, the GHR, PRLR) (Fig. 3, Supplemental Fig. 1). They also include archetypal STAT was duplicated locally early in chordate homodimeric group 2 CytoRs (G-CSFR, LEPR), heterodimeric evolution, but the action of the two WGDs resulted in the complexes of different group 2 receptor chains (LIFR, IL-12R, generation of six STATs from these in two distinct subfam- IL-23R, IL-27R, IL-35R), and group 2/group 3 heterodimeric ilies (precursors to mammalian STAT1–4 and STAT5–6) (34, (IL-6R, IL-11R) and heterotrimeric (CNTFR) complexes, all of 37).TheIRF9componentofthevariantheteromericSTAT which use GP130 or a related receptor for signal transduction complex activated in response to IFNs was also generated (Fig. 3, Supplemental Fig. 2). For heterodimeric group 4/group during this time frame (59). Finally, the archetypal SHP was 5 receptors, the core members notably include several using the expanded to two members (precursors of higher vertebrate common IL-2Rgc signaling chain (IL-4R, IL-7R, IL-21R and SHP1–2), whereas the three original SOCS genes expanded to The Journal of Immunology 15 Downloaded from http://www.jimmunol.org/

FIGURE 3. Functional specialization and diversification of CytoR signaling. Summary of the deduced CytoRs and their key roles across key stages of evolution, assuming conserved complex formation and function with mammalian CytoRs, showing both specialization and diversification. The “core” CytoR complexes of bilateria and gnathostomata are shown according to class, cytokine type, and complex topologies, with receptor chains color coded: class I: group 1 (red), group 2 (dark blue), group 3 (light blue), group 4 (dark green), group 5 (light green), sushi domain-based (black); class II: long IFNR chain (brown), short type I IFNR (pink), short type II IFNR (purple), long IL-10R–related chain (gray), short IL-10–related chain (orange). Individual receptors are shown below the relevant topology, and the major function(s) of each are indicated according to the key. Other CHD-containing cytokine-binding components are also presented. The subsequent evolution of these core CytoRs along the teleost and tetrapod/mammal lineages is shown along with known functions. by guest on September 24, 2021 create precursors to all eight SOCS types, most likely via the vertebrate evolution (Fig. 2, Supplemental Figs. 1–4). Prior to WGDs (10, 37). the divergence of ray-finned fish (including teleost fish, such Functions of the core CytoR pathway. Available evidence suggests as zebrafish) and lobe-finned fish (including tetrapods, such as that the functions mediated via the majority of these “core” CytoRs humans), limited additional components evolved, with avail- have been conserved. For example, analysis in zebrafish showed able data suggesting just the ligand-specific receptor chain for that GHR functions in controlling growth (60), LEPR functions OSMR and the negative regulator SHP3, as well as a potential in metabolic control (61), G-CSFR participates in myelopoiesis partial precursor of TSLPR, probably by local duplication. (62), IL-7R contributes to T cell development (63) and type II Along the tetrapod lineage, local duplication subsequently IFNR participates in antiviral responses (64), similar to their generated the distinct ligand-specific chains for IL-2R and mammaliancounterparts.Thiswasshowntoextendtotheir IL-15R, as well as IL-3R and GM-CSFR, along with a bona downstream pathways where investigated, such as EPOR/JAK2/ fide ligand-specific TSLPR chain (55). There has been a STAT5 in erythropoiesis (65, 66) and IL-2Rgc/JAK3/STAT5 in concomitant increase in the cognate cytokines for these re- T lymphopoiesis (67). Although therearesomeexceptions[e.g., ceptors (55, 56), whereas the diversity of type I and type III PRLR, which functions in mammopoiesis, lactogenesis, and IFNs has also increased (51, 72). However, downstream reproduction in mammals (68, 69)butfunctionsinosmoregu- components remain largely unaltered, with the exception of lation and retinal development (70, 71) in teleosts], it remains the duplication of a single STAT (STAT5) in mammals and reasonable to deduce the likely functions of the core receptors loss of SHP3, which remains as a pseudogene (37). In con- (Fig. 3). This indicates a strong trend toward specialization of trast, within the teleost lineage there was an additional round functions with regard to a particular cell system (innate immu- of WGD ∼305–450 million years ago (73), which largely nity, hematopoiesis, neurogenesis, stem cell maintenance, and underpinned the duplication of many components, includ- control of growth and metabolism) and, indeed, to particular ing several receptor chains (PRLR, GHR, LIFRa, IL-2Rgc, subsets within these (e.g., EPOR in erythropoiesis, G-CSFR in IFNgR, and the noncanonical TF) (20, 74), whereas local myelopoiesis). It has also underpinned the development of new duplications created an additional IL-12Rb2, IL-4Ra,and functions, most notably in adaptive immunity. the novel somatolactin receptor, as well as alternate type I IFNRs. Conversely, there was a loss of ligand-specific chains Diversification of the pathway that complex with IL-3Rbc and that form the type III IFNR, Having established a core group of CytoR–JAK–STAT path- along with their ligands (20, 53). In addition, duplicates for one ways, additional diversification occurred during subsequent JAK (JAK2), two STATs (STAT1, STAT5), and several SOCSs of 16 BRIEF REVIEWS: CYTOKINE RECEPTOR EVOLUTION particular relevance to CytoR signaling (SOCS1, SOCS3, CISH) Moreover, during the diversification phase, the additional were also generated through the additional WGD (37). Although receptor complexes generated in the tetrapod/mammalian the analysis remains incomplete, it is also clear that numerous lineage (TSLPR, IL-2R, IL-15R, IL-3R, GM-CSFR) all use cytokines (including IL-11, G-CSFR, leptin, and multiple STAT5, which was also duplicated along this lineage. Simi- IFNs) were duplicated by a variety of mechanisms (50, 51, 56, larly, many of those duplicates generated in teleosts use JAK2 57, 72). How these components are used within functional (PRLR, GHR, type II IFNR), and most act via STAT5 CytoR signaling pathways remains to be determined. (PRLR, GHR, IL-2Rgc) or STAT1 (type I and II IFNRs), with several regulated by SOCS1, SOCS3, and CISH, all of Outcomes. The ongoing diversification of CytoR–JAK–STAT which have been duplicated in this lineage. components observed in higher vertebrates has been relatively The evolution of CytoR signaling, including a complex array minor. However, it has likely underpinned increased so- of cytokines, CytoR chains, and downstream signaling mol- phistication in the tetrapod/mammalian immune system ecules, requires strong selective pressures. One major driver is through the unique contributions to hematopoiesis and likely to be the powerful selective advantage of a robust and immunity mediated by TSLPR (75)—and potentially IL- multifaceted immune system in which many of the CytoRs 9R (76)—as well as the distinct functions of IL-2R exert their influence (37, 72, 98) (Fig. 3). This is consistent compared with IL-15R (77, 78) and of IL-3R compared with the emergence of the CytoR–JAK–STAT signaling with GM-CSFR (79). However, among immune-related pathway being coincident with the evolution of primitive CytoRs, the increased complexity appears similar in teleosts, multilineage innate immune cells, the function of which is Downloaded from suggesting comparable sophistication in this lineage, although influenced by this pathway, as exemplified in present-day fruit this has not been confirmed experimentally. The diversification fly (45). It is further supported by the major expansion of the also appears to reflect some lineage-specific environmental CytoR–JAK–STAT pathway being concurrent with the de- adaptations. For example, the divergence in IFNRs likely velopment of a sophisticated adaptive immune system during reflects the different pathogen spectrum and dynamics development (72, 98). This is supported by the extensive between water-dwelling teleosts and largely land-dwelling retention of WGD-generated duplicates of CytoR signaling http://www.jimmunol.org/ tetrapods (80). The role for the somatolactin receptor in components compared with the average retention rate of just body color regulation (81) and PRLR in osmoregulation 3–4% (73) and is consistent with other studies indicating that (70) within teleosts also falls into this category. WGDs played a crucial role in adaptive immunity by providing Consequences and drivers new genetic materials for a range of essential components (99). The evolutionary history of the CytoR–JAK–STAT pathway Additional evidence for immunity as a key driver can be gleaned provides insights into the function(s) observed for individual from the significant divergence in the IFN-responsive CytoRs CytoRs in specific lineages (Fig. 3). Thus, the archetypal between teleosts and tetrapods (51), likely as a result of the pathway, which was based on a GP130-related CytoR, likely powerful selective forces associated with combatting ever- by guest on September 24, 2021 possessed diverse and pleiotropic functions, including in he- changing pathogens, particularly viruses, which develop sub- matopoiesis, innate immunity, neurogenesis, stem cell main- version mechanisms to counter the antiviral effects of IFNs in tenance, and the control of growth and metabolism, as seen in fish and mammals (53, 80, 100). This is borne out, for ex- extant insects (42, 43, 45–47, 82). This probably formed the ample, by other data showing that the majority of type I IFNs basis for the functional diversity, pleiotropy, and redundancy have been subjected to purifying selection (101). However, of the CytoRs found in higher vertebrates (83), such as the selective pressures outside of immunity also likely contributed pleiotropic functions of IL-6R (84) and LIFR (85); the spe- to the evolution of the CytoR pathway, such as the need for cialist hematopoietic functions of EPOR (65, 86), G-CSFR functional specialization as organismal complexity increases to (20, 87, 88), and TPOR (89); the innate immunity roles of provide fine tuning of specific biological processes. type I and III IFNs (90, 91); the stem cell functions of TPOR (92); the neural functions of CNTFR (93); and the roles of GHR, PRLR, and LEPR in growth, metabolism, and repro- Conclusions This review highlights the long and complex evolutionary history duction (68, 94, 95). The increase in components allowed of the class I and class II CytoR signaling paradigm. This is one major additional functionality to emerge, with the IL-2R reflected in the myriad roles played by numerous CytoR–JAK– and IL-3R families and type II IFNs exerting their major STAT modules across diverse extant species, but especially the effects in adaptive immunity (63, 67, 74, 96). In addition, key conserved roles in immune and blood cell development and downstream components originally played pleiotropic roles function. This history can be divided into three broad stages: (97), a property that has been maintained particularly in JAK1, JAK2, STAT3, STAT5, and SOCS3, although other Emergence: The generation of individual CytoR–JAK–STAT duplicates have developed more specific roles, such as JAK3, pathway components largely by accretion of pre-existing do- STAT4, and STAT6 in adaptive immunity and TYK2, mains and their subsequent coalescence into a complete sig- STAT1, STAT2, and SOCS1 in antiviral immunity (5). naling module. This archetypal pathway had diverse and Interestingly, but perhaps not surprisingly, the evolution of pleiotropic functions, including a role in innate immunity. CytoRs is paralleled in the downstream signaling molecules, Expansion: The rapid increase in components during early such that expansion of particular CytoRs appears to be a strong vertebrate evolution principally driven by two rounds of driver of the increase in relevant downstream components (37). WGD that ultimately produced core representatives for Thus, the expansion phase that generated all major receptor each of the major CytoR groups, along with their cog- types also generated all types of JAKs, STATs, SHPs, and nate ligands, and the majority of JAK, STAT, and key SOCSs required to provide functional specificity downstream. negative-regulatory components. This was associated with The Journal of Immunology 17

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