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Review TRENDS in Plant Science Vol.9 No.2 February 2004 Brassinosteroid signal transduction – choices of signals and receptors Zhi-Yong Wang and Jun-Xian He Department of Plant Biology, Carnegie Institution, 260 Panama Street, Stanford, CA 94305, USA Small signaling molecules that mediate cell–cell communication are essential for developmental regulation in multicellular organisms. Among them are the steroids and peptide hormones that regulate growth in both plants and animals. In plants, brassinosteroids (BRs) are perceived by the cell surface receptor kinase BRI1, which is distinct from the animal steroid receptors. Identification of components of the BR signaling pathway has revealed similarities to other animal and plant signal transduction pathways. Recent studies demonstrated that tomato BRI1 (tBRI1) perceives both BR and the peptide hormone systemin, raising new questions about the molecular mechanism and evolution of receptor –ligand specificity. All multicellular organisms have evolved mechanisms to perceive and respond to extracellular chemical signals, including endogenous hormones and external cues from the environment, pathogens and symbiotic organisms. Among these signaling molecules, steroids and small peptides are widely used in both animals and plants [1,2]. Although plant and animal steroids have many similarities in biosynthesis and function, the molecular mechanisms of steroid perception and signal transduction appear to be different in the two kingdoms. The plant steroid hormones brassinosteroids (BRs) are perceived by the cell surface receptor kinase BRI1 [3]. By contrast, most animal steroid responses are mediated by the nuclear receptor family of transcription factors [4]. Although some animal steroid responses are mediated by cell surface receptors [5], recent cloning of membrane-bound steroid receptors in fish and mammals indicated that they are similar to the G-protein-coupled receptors [6,7] but distinct from the BR receptors. However, the BR signaling pathway shares features with peptide hormone signaling pathways in animals and plants. Recent studies in tomato demonstrated that tomato BRI1 (tBRI1) functions as the receptor for both BR and systemin, a peptide hormone that mediates systemic responses to wounding by insect pests [8]. These studies raise the possibility of conserved interaction among the BR signaling, defense response and peptide signaling pathways. Our aim here is to highlight the latest findings in BR and related signaling pathways that can provide some insight into the molecular mechanism of BR signal transduction and plant growth regulation. Corresponding author: Zhi-Yong Wang ([email protected]). Genetic studies identified brassinosteroid signaling components BRs are a class of plant steroid hormones with important regulatory roles in multiple developmental and physiological processes, including seed germination, stem elongation, leaf expansion, xylem differentiation, disease resistance and stress tolerance [9 – 11]. BR-deficient and -insensitive mutants show various developmental defects, including reduced seed germination, dwarfism, dark-green and curled leaves, reduced fertility, delayed reproductive development, and development of lightgrown morphology (de-etiolation) in the dark [3]. Similar phenotypes can be caused by BR biosynthetic inhibitors, such as brassinazole (Brz) [12]. By contrast, overexpression of BR biosynthetic enzymes and the BRI1 receptor increases cell elongation and plant growth [13,14]. Molecular genetic studies of BR response mutants in Arabidopsis have led to the identification of a BR receptor and downstream signaling components. Genetic screens for BR-insensitive mutants have identified multiple alleles of the bri1 [15,16] and bin2 loci [17 – 19], which led to the identification of BRI1 as the BR receptor [16] and BIN2 as a negative downstream regulator [20]. BR-insensitive mutants have also been identified in other species, including pea [3], rice [21], barley [22] and tomato [23], and these mutants have been found to contain mutations in the BRI1 homologs. The det3 mutant also has dwarf and de-etiolated phenotypes, and is partially insensitive to BR. DET3 encodes a subunit of the vacuolar Hþ-ATPase (V-ATPase), suggesting that V-ATPase activity is involved in the BR response [24]. Mutants that suppress BR-deficient or -insensitive phenotypes have also been identified in various genetic screens. An activation-tagging screen for suppressors of the weak bri1-5 allele identified genes that promote BR response when overexpressed. These include the BRS1 gene, which encodes a putative serine carboxypeptidase [25], and the BAK1 gene, which encodes a leucine-richrepeat (LRR) receptor kinase [26]. BAK1 was also identified as a BRI1 interacting protein [27]. Genetic screens for mutants insensitive to the BR biosynthetic inhibitor Brz and for bri1 suppressors identified the brassinazole resistant1-D (bzr1-1D) and bri1 EMS suppressor (bes1-D) mutants, respectively [28,29]. Cloning of BZR1 revealed a close homolog in Arabidopsis named BZR2, and subsequent sequencing of the BZR2 gene in the bes1-D mutant revealed that mutations of the same amino acid residue in BZR1 and BZR2 were responsible for the www.sciencedirect.com 1360-1385/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tplants.2003.12.009 Review 92 TRENDS in Plant Science bzr1-1D and bes1-D mutants, respectively [28,29]. These studies identified BZR1 and BZR2/BES1 as two homologous nuclear proteins that play overlapping yet distinct roles in BR signaling [28,29] (Figure 1). Brassinosteroid receptors BRI1 is an LRR receptor-like kinase (LRR-RLK) located on the cell surface [16]. BRI1 has an extracellular domain containing 25 LRRs, a transmembrane domain, and a cytoplasmic serine/threonine kinase domain [30,31]. It has been shown that BRI1 immunoprecipitates with BR binding activity and BR induces autophosphorylation of BRI1 in vivo [13]. Furthermore, BR binding and kinase activation is abolished by a mutation in the extracellular domain of BRI1 [13]. These experiments demonstrate that BRI1 perceives the BR signal through its extracellular domain and initiates a signal transduction cascade through its cytoplasmic kinase activity [13,32]. BAK1 is potentially another component of the BR receptor complex [26,27,33]. BAK1 interacts with BRI1 in vitro and in vivo, and they phosphorylate each other in vitro. Results of both gain-of-function and loss-offunction experiments support a positive role for BAK1 in BR signaling [33]. The molecular mechanism by which BR activates the receptor kinases is unclear. Although in vivo interaction between BRI1 and BAK1 has been detected, the effect of BR on this interaction is not known. Thus, the hypothesis remains to be tested that ligand binding might BR ? BAK1 BRS1 BRI1 ? BR BR synthesis CPD BIN2 BZR1 BZR2/BES1 + P BR-regulated gene expression V-ATPase BZR1– P BZR2/BES1– P Degradation by proteasome Cell wall enzymes Growth response TRENDS in Plant Science Figure 1. A diagram of the brassinosteroid (BR) signal transduction pathway in Arabidopsis. BR is perceived by the receptor complex containing BRI1 and BAK1, which are leucine-rich-repeat receptor-like kinases (LRR-RLKs) that interact with each other. Activation of the receptor kinases by BR binding leads to the dephosphorylation and accumulation of the nuclear proteins BZR1 and BZR2/BES1, possibly by inhibiting the negative regulator BIN2. In the absence of BR, the BIN2 kinase phosphorylates BZR1 and BZR2/BES1, and targets them for degradation by the ubiquitin-dependent proteasome pathway. BZR1 and BZR2/BES1 regulate BRtarget genes differently; these targets include the BR biosynthetic gene CPD, which is feedback inhibited by BR through BZR1, and genes encoding enzymes for cell wall synthesis that are probably regulated by both BZR1 and BZR2/BES1. The vacuolar Hþ-ATPase (V-ATPase) is also a mediator of certain BR responses. The serine carboxypeptidase BRS1 is proposed to process an unknown extracellular factor that contribute to the activation of the BR receptors. www.sciencedirect.com Vol.9 No.2 February 2004 activate the kinases by inducing receptor heterodimerization, as known for the receptor tyrosine kinases and the transforming growth factor b receptor kinases in animals [26,33]. Because BR binding activity was not detected for recombinant BRI1 proteins expressed in non-plant cells [13] and BR treatment did not increase receptor phosphorylation nor association between BRI1 and BAK1 coexpressed in yeast cells [27], it is believed that either proper modification of the receptor kinases or additional proteins are required for BR binding and signaling. The BRS1 serine carboxypeptidase has been proposed to proteolytically process an extracellular component of the BR receptor complex [25]. Biochemical purification of all proteins associated with the BRI1 –BAK1 receptor kinase complex should provide further insight into the molecular mechanism of the BR receptor function. Downstream brassinosteroid signaling Although the direct substrates of BRI1 and BAK1 are unknown, components further downstream have been identified. BIN2 encodes a cytoplasmic protein kinase homologous to the Drosophila SHAGGY kinase and the mammalian glycogen synthase kinase 3 (GSK3) [20]. Genetic studies indicated that BIN2 is a negative regulator in the BR signaling pathway, similar to most SHAGGY/GSK3 kinases in animal systems [18,20]. Two nuclear proteins, BZR1 and BES1, were recently identified as positive regulators of the BR signaling pathway downstream of bin2. The accumulation of BZR1 and BES1 is increased by BR treatment and by the same mis-sense mutations in bzr1-1D and bes1-D, which suppress the bri1 and bin2 mutants [28,29]. BZR1 and BES1 are mostly in phosphorylated forms, and BR treatment induces dephosphorylation and accumulation of the proteins [28,29]. Biochemical studies indicate that BIN2 directly phosphorylates and destabilizes BZR1 and BES1 [29,34,35]. BIN2 interacts with BZR1 and BES1 in yeast two-hybrid assays and phosphorylates them in vitro. In the gain-offunction bin2 mutant, the accumulation of BZR1 and BES1 is decreased and their BR-induced dephosphorylation is attenuated [29,34]. Phosphorylated BZR1 appears to be degraded by the 26S proteasome, because treatment of seedlings with the proteasome inhibitor MG132 preferentially increased the accumulation of the phosphorylated BZR1 protein [34]. MG132 treatment did not alter the kinetics of BR-induced BZR1 dephosphorylation, suggesting that BZR1 might be dephosphorylated by a phosphatase [34]. These studies illustrate a BR signal transduction pathway leading from the cell surface receptors to the nucleus (Figure 1). BR activation of the BRI1– BAK1 receptor kinases inhibits BIN2 through an unknown mechanism, allowing accumulation of unphosphorylated BZR1 and BES1, which in turn regulate BR target genes in the nucleus [29,34]. In the absence of BR, BIN2 kinase inhibits downstream BR responses by phosphorylating BZR1 and BES1, and targeting them for degradation by the proteasome (Figure 1) [34]. The regulation of BZR1 and BES1 degradation by BIN2 phosphorylation is similar to several signaling pathways in both animals and plants. Review TRENDS in Plant Science Particularly, the structural homology between BIN2 and GSK3 highlights the similarity to the Wnt signaling pathway in animals [36]. However, regulated degradation of nuclear factors by the proteasome has been observed in various plant signaling pathways and has emerged as a common theme of signal transduction in plants (Table 1). The biochemical function of BZR1 and BES1 has yet to be determined. It is unclear whether BR regulates transport of BZR1 and BES1 into the nucleus [28,29,35]. Both bzr1-1D and bes1-D mutants have altered expression of BR-regulated genes [28,29], but it is not known whether BZR1 and BES1 directly bind to DNA or regulate gene expression by interacting with DNA-binding proteins. The different phenotypes of light-grown bzr1-1D and bes1-D suggest that the two proteins have overlapping yet distinct functions and thus should have different downstream targets. A better understanding of the functions of the BZR1 and BES1 proteins should be achieved by identifying their interacting proteins, which could include the phosphatase that dephosphorylates them, the ubiquitin ligase that targets the phosphorylated BZR1 and BES1 for ubiquitination and degradation, and possibly transcription factors that interact with BR-regulated promoters. Tomato BRI1 has dual functions as receptor of brassinosteroid and systemin A similar BR signaling mechanism is apparently conserved in other plants because mutations in BRI1 homologs are responsible for BR-insensitive mutant phenotypes in pea [3], rice [21], barley [22] and tomato [23]. Interestingly, recent studies in tomato demonstrated that tBRI1 is not only required for BR response but also functions as the receptor for systemin [37], which is a peptide hormone that mediates systemic wound responses in tomato partly through inducing jasmonic acid synthesis [38]. Using radiolabeled systemin, Justin Scheer et al. identified a 160-kDa plasma membrane protein that bound systemin with high affinity [39], and purified a putative systemin binding protein using photoaffinity labeling [37]. Surprisingly, the identified protein, SR160, was most homologous to BRI1 in Arabidopsis [37], and mutations in this gene were later found in the tomato BR-insensitive mutants altered brassinolide sensitivity1 (abs1) and curl3 (cu3) [23], indicating that SR160 is the BRI1 ortholog tBRI1 [23]. Scheer et al. have recently confirmed that tBRI1/SR160 is the systemin receptor by expressing the tomato systemin in tobacco and analysing systemin response in the cu3 mutant [8]. Systemin is present only in members of 93 Vol.9 No.2 February 2004 the Solaneae subtribe of Solanaceae family, including tomato and potato, and is absent from tobacco, a member of the Nicotianae subtribe. Wild-type tobacco has neither binding activity nor response to tomato systemin. However, tobacco cells transformed with the tomato tBRI1/ SR160 gene showed systemin binding activity and a systemin-induced alkalinization response, similar to that of tomato cells [8]. These results indicate that tBRI1/ SR160 is sufficient to confer systemin responsiveness on tobacco and that the downstream components of the systemin signaling pathway are present in tobacco [38]. Furthermore, the BR-insensitive tomato line cu3 has greatly reduced response to systemin [8]. Although BR does not inhibit systemin binding to tBRI1 in suspensioncultured tomato cells [37], it reversibly antagonized systemin response in tomato leaves [8]. These studies have established that tBRI1/SR160 functions as receptor for both BR and systemin [8]. This exciting conclusion raises many interesting questions. For example, how can one receptor kinase perceive two hormones with such different physiological functions [40], and how is specificity achieved for both ligand recognition and downstream signaling? Furthermore, why does systemin use BRI1 among the hundreds of LRR-RLKs in plants? Is tBRI1 a special case or are BR receptors of other plants also bifunctional, perceiving both steroidal and peptide ligands? One receptor for two signals The only other receptor known to perceive two types of ligands is the mammalian oxytocin receptor (OTR), a member of the G-protein-coupled-receptor family. OTR binds to both the peptide hormone oxytocin and the steroid hormone progesterone [41]. In this case, oxytocin and progesterone antagonistically regulate similar physiological responses by competing for binding to the same receptor [41]. The regulation of BRI1 by BR and systemin appears to involve a mechanism different from the oxytocin – progesterone systems. First, loss-of-function mutation of tBRI1 inactivates both BR and systemin responses, indicating that BRI1 is a positive regulator for both pathways and should be activated by both ligands [8]. Second, BR does not reduce systemin binding [37] but does inhibit the systemin response [8], suggesting that BR binds to different ligand-binding sites and inhibits systemin response by recruiting tBRI1 from the systemin pathway into the BR signaling pathway (Figure 2). If systemin competes with BR for tBRI1, one might expect systemin to act as an inhibitor of growth. Interestingly, the transgenic tomato plants that overexpress the Table 1. Common theme in plant signal transduction – signal for degradation of key nuclear regulators by the proteasome Signals Nuclear factor and functiona E3 ligase Effect of the signal Refs Brassinosteroid Auxin BZR1 (þ) Aux and IAAs (2 ) NAC1 (þ) GAI, RGA and SLN1 (2 ) ABI5 (þ) Unknown Hy5 (þ) Unknown TIR1 SINAT5 SLY1 AFP?b COI1 COP1 Accumulation Degradation Accumulation Degradation Accumulation Unknown Accumulation [34] [55] [56] [57,58] [59] [60] [61] Gibberellins Abscisic acid Jasmonic acid Light a Activation of plant signal transduction pathways often leads to degradation of repressors (2) or accumulation of activators (þ ) in the nucleus by regulating the interaction between the nuclear protein and specific ubiquitin E3 ligases that promote its ubiquitination and degradation by the proteasome. The biochemical function of AFP is unknown. b www.sciencedirect.com Review 94 TRENDS in Plant Science Vol.9 No.2 February 2004 (b) Tomato (a) Drosophila Wounding Pathogen or developmental signals Spaetzle BR BR Toll Systemin Prosystemin Pro-Spaetzle BAK1? tBRI1 ? tBRI1 Pelle Plasma membrane tBRI1 JA Embryo polarity Defense response Cell wall synthesis Growth responses Defense response TRENDS in Plant Science Figure 2. The similarities between the brassinosteroid (BR) and systemin signaling pathways in tomato and the Toll signaling pathways in Drosophila. (a) The Toll signaling pathway controls both embryonic development and innate immunity in Drosophila. Toll is a large transmembrane receptor with an N-terminal extracellular leucine-richrepeat (LRR) region similar to that of the BRI1 receptor kinase in plants and a C-terminal intracellular (TIR) domain. Toll is activated by binding of its ligand Spaetzle. Spaetzle is synthesized as an inactive precursor, which is processed and activated by proteases generated either during embryo development or upon pathogen invasion of adult flies. The binding of Spaetzle to Toll induces dimerization of the receptor and activation of the downstream kinase Pelle, a serine/threonine kinase evolutionarily related to the kinase domain of BRI1. Activation of Pelle leads to dorsoventral polarity gene expression during embryo development and defense gene expression in innate immune responses of adult flies. (b) BR signaling (left) and systemin signaling (right) pathways in tomato. tBRI1 perceives both BR and systemin signals. BR interacts with the extracellular domain of BRI1 and activates the kinase activity of BRI1, initiating a signaling cascade that leads to BR-regulated gene expression and growth responses. The tBRI1 receptor complex might also contain BAK1. Systemin is produced from a precursor protein prosystemin by proteolytic processing upon wounding. Systemin binds to the tBRI1 to initiate a signaling pathway that leads to systemic defense responses by inducing jasmonic acid (JA) synthesis. Jasmonic acid also feeds back to induce systemin and tBRI1, further amplifying and spreading the signals. BR inhibits systemin responses, suggesting that the two signals compete for the receptor to regulate developmental or defense responses. pro-systemin gene (35S-Prosys) have significantly longer hypocotyls than wild-type plants [42], suggesting that systemin promotes seedling growth. However, the longhypocotyl phenotype of 35S-Prosys plants is unlikely to be caused by direct activation of the BR signaling pathway. Mutants that suppress the accumulation of protease inhibitors also suppress the long-hypocotyl phenotype of 35S-Prosys tomato. These include the suppressors of prosystemin-mediated responses 2 (spr2) mutant, which is blocked in jasmonic acid biosynthesis [43], suggesting that prosystemin promotes growth through a jasmonic acid-dependent pathway. Jasmonic acid might affect growth directly or by feedback regulating systemin and tBRI1 activity. Jasmonic acid feedback activates prosystemin [38,44] and systemin binding activity [39] to amplify and spread the systemic signals efficiently. The specificity of downstream responses might vary with developmental stages, as known for the dual-functional Drosophila Toll receptor (see below). of Dorsal nuclear localization, leading to embryonic polarity [47]. In innate immunity of adult flies, recognition of bacteria and fungi by the peptidoglycan-recognition proteins triggers a proteolytic cascade that ultimately cleaves inactive Spaetzle into a shortened activated form, which activates Toll and leads to the production of antimicrobial peptides that mediate defense [48]. In addition to Spaetzle and Toll, some downstream components (Tube, Pelle and Cactus) are required for both developmental and defense responses [45]. Active Spaetzle binds to Toll directly with high affinity and with a stoichiometry of one Spaetzle dimer to two receptors, thus activating Toll by inducing receptor dimerization [49]. The dual function of tBRI1 in developmental and defense responses is thus similar to Toll. Unlike Toll, which is activated by the same ligand Spaetzle, tBRI1 apparently perceives both BR and systemin. Thus, tBRI1 appears to be the only receptor known to be activated by two signals that lead to two distinct responses. One receptor for two responses The dual function of tBRI1 is similar to that of the Drosophila receptor Toll, which also has an extracellular LRR domain structurally similar to that of BRI1. Toll is essential for establishing dorsoventral patterning in embryos as well as for innate immune defenses to fungi and bacteria in adult flies [45]. During embryo development, binding of Toll by its ligand Spaetzle leads to activation of the Pelle kinase, which is evolutionarily related to the kinase domain of BRI1 [46], and nuclear translocation of the transcription factor Dorsal. The asymmetric generation of Spaetzle results in a gradient Perspectives and prospects LRR-containing receptors are conserved in plants, insects and mammals for mediating innate immunity [50,51]. Homologs of Toll (Toll-like receptors, TLRs) have been found in mammals to mediate both innate and adaptive immune responses. Mammalian TLRs perceive not only exogenous molecules from microorganisms but also endogenous agonists such as the degradation products of macromolecules, products of proteolytic cascades and intracellular components of ruptured cells [52]. It has been proposed that TLRs represent an ancient mechanism of perceiving environmental challenges and cellular www.sciencedirect.com Review TRENDS in Plant Science damage [52]. Whereas most animals have fewer than a dozen LRR receptors, plants have evolved with an expanded family of more than 500 LRR proteins. These include , 210 Arabidopsis LRR-RLKs containing a cytoplasmic kinase domain related to Pelle [46], some of which are known to function in disease resistance [53] and developmental regulation [54]. The dual function of tBRI1 might represent an evolutionarily conserved mechanism. It has been proposed that BRI1 might have a defensive role that was co-opted by systemin during evolution in the Solaneae subtribe of the Solanaceae family [38]. Although systemin is only found in a subtribe of Solanaceae plants, various peptides that induce similar cellular responses have been found in other plants [38], and proteolytic processing of peptides has been implicated in BR signaling in Arabidopsis [25]. It is possible that BRI1 in Arabidopsis and other plants also perceives peptide signals and has a role in defense. Whereas it might be wise for Drosophila to use one receptor efficiently for two responses, it is surprising that the dual functions of tBRI1 have not separated after such dramatic expansion of this receptor gene family in plants. There is possibly a benefit for coupling BR and wounding signals with one receptor, such as coordinating cell expansion with cell wall synthesis in order to avoid cell rupture. Signals generated by cell damage can regulate either cell wall synthesis or defense responses, perhaps depending on the developmental stage of the tissue. Systemin might have evolved recently from a local wounding signal that became jasmonic acid inducible or from a jasmonic acidinduced peptide that acquired tBRI1 binding activity. Further studies of BR and systemin signaling in tomato will shed light on the specificities of LRR-RLKs at the levels of both ligand binding and downstream signaling. Like the Toll pathway, some of the downstream components might also be shared between BR and systemin responses, and it will be interesting to determine whether BAK1, BIN2, BZR1 and BES1 play roles in systemin signaling. Conversely, analysis of BR responses of the other systemin-related tomato mutants and identification of systemin signaling components will provide a better understanding of how the specificity of downstream signaling is achieved. The questions about the mechanism of dual function remain to be answered by further studies of the BRI1 receptor complex. Perhaps a more important question is whether the dual function has been evolutionarily conserved. The wound and BR responses are two of the best-studied plant signaling pathways, and their merging promises to bring more excitement in the future. Acknowledgements We thank David Ehrhardt, Yu Sun and Zhiping Deng for critical reading of the manuscript. 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