The Plant Hippo Pathway: An Evolved Hub for Strategic Resource Allocation Governing Growth-Defense-Reproduction Trade-offs

For sessile plants, survival hinges on the dynamic allocation of limited resources among growth, defense, and reproduction. We propose that the plant Hippo signaling network has evolved into a central strategic hub governing these fundamental trade-offs. Building upon its evolutionarily conserved pleiotropic roles, this hub in plants has acquired unique regulatory capacities. It integrates hormonal, developmental, and stress signals to act as a cellular decision-maker, moving beyond the paradigm of a linear growth regulator. Plant-specific innovations—including a direct SIK1-MOB1 interaction that bypasses the canonical SAV1 scaffold, dual-specificity NDR kinases, and MOB1A/B heterodimer formation—underpin this adaptive evolution. Crucially, the antagonism between SIK1 and MOB1 fine-tunes the jasmonate pathway, functioning as a molecular “rheostat” for the growth-defense balance. Viewing the plant Hippo pathway through the lens of “adaptive trade-off management” not only redefines its biological significance but also charts a new research agenda. We outline priorities to quantify signal flux through the hub, resolve the structure of plant-specific complexes, and manipulate this decision-making system to engineer crops with optimized resilience and yield.

The Hippo pathway is an ancient and conserved eukaryotic kinase cascade, fundamental to multicellular life. First discovered in Drosophila as a regulator of organ size (Wu et al., 2003), its canonical core—a kinase cascade module (GCK→NDR) with scaffold proteins (SAV1, MOB1)—orchestrates cell proliferation, apoptosis, and stem cell fate to maintain tissue homeostasis, repair, and regeneration across animals (Harvey & Hariharan, 2012; Halder & Johnson, 2011). Its dysregulation is a hallmark of cancers and other diseases, underscoring its role as a guardian of developmental integrity (Tang et al., 2022). Notably, this pathway is not a simple linear cascade but exhibits organizational complexity, with parallel branches (e.g., the Drosophila FRY/TRC pathway, mammalian HPO1/HPO2 modules) fine-tuning outputs for specific contexts (Avruch et al., 2012; Zhong et al., 2023) (Fig. 1). This deep evolutionary conservation extends to yeast, where analogous GCK→NDR modules govern distinct processes like mitotic exit (MEN) and cellular morphogenesis (RAM) (Nelson et al., 2003; Baro et al., 2017) (Fig. 1). In plants, orthologs of the core Hippo components were identified shortly after their discovery in animals. However, research has long been guided by animal-centric paradigms of growth control and homeostasis, a perspective compounded by fragmented nomenclature (e.g., ”RAM/MOR” vs. ”Hippo”). While an emerging model also suggests parallel signaling branches in plants, analogous to those in yeast (Zermiani et al., 2015) (Fig. 1), a critical conceptual gap persists. The prevailing view fails to explain the pathway’s pleiotropic roles in seemingly disparate plant processes—from reproduction and organogenesis to immunity and hormonal crosstalk. This raises a fundamental question: How is this deeply conserved signaling toolkit utilized to meet the unique existential challenges of a sessile organism? We propose that the plant Hippo pathway has undergone a profound evolutionary repurposing. Beyond its ancestral role in coordinating cellular behaviors, we synthesize recent evidence to argue that it has been rewired into a central strategic hub for managing external resource allocation (Zhang et al., 2017, 2018; Guo et al., 2020; Zhou et al., 2021). For sessile plants, evolutionary fitness hinges on the dynamic and often conflicting demands of growth, defense, and reproduction. We posit that the plant Hippo network functions as a master regulator of these critical life-history trade-offs. This capability is enabled by distinct, plant-specific molecular innovations—such as a direct SIK1-MOB1 interaction bypassing the canonical SAV1 scaffold (Xiong et al., 2016), dual-specificity phosphorylation by NDR kinases (Katayama et al., 2012), and the formation of a potent MOB1A/B heterodimer (Guo et al., 2020). These adaptations transform the conserved kinase module into a versatile decision-making platform. This hub integrates hormonal, developmental, and stress signals, acting as a cellular strategist. A prime example is the quantitative antagonism between the upstream integrator SIK1 and the central processor MOB1, which fine-tunes the jasmonate pathway like a molecular ”rheostat” to dynamically balance investment in growth versus defense (Huang et al., 2017). In this review, we articulate this paradigm shift. We will detail the evidence supporting this ”signaling hub” model, highlighting how a core set of innovated components—SIK1 (the upstream integrator and gateway), MOB1 (the central processor and hormonal balancer), NDR (the bimodal executor), MO25 (the programmable adaptor platform), and FRY (a putative signal processor)—collectively constitute this strategic system. By synthesizing their unique mechanisms, we aim to provide a unified conceptual framework that explains the pathway’s diverse functions. Finally, we will outline a forward-looking research agenda to decipher the hub’s operational logic, with the ultimate goal of leveraging these insights for the rational design of future crops. 2. The Core of the Hub: From Conserved Module to Strategic Integrator The plant Hippo hub is built upon the conserved eukaryotic GCK-NDR kinase module. Its transformation into a strategic resource-allocation center, however, is driven by specific innovations within five core components: SIK1, MOB1, NDR, MO25, and FRY. While the architectural parallels to animal branches are still being mapped, the integrated function of these components is evident (Zermiani et al., 2015; Tian et al., 2023). The following sections will demonstrate how plant-specific adaptations in each of these proteins—reconfiguring interactions, enzymatic activity, and complex formation—collectively rewire the ancestral module. This rewiring enables the pathway to integrate diverse signals and execute the fundamental trade-offs between growth, defense, and reproduction. 2.1 SIK1: The Upstream Integrator and Gateway of the Hub Positioned at the apex of the signaling network, SIK1 functions as the primary sensory and integrative node of the plant Hippo hub. It exemplifies how a deeply conserved STE20-like kinase has been structurally and functionally adapted to meet the unique signaling demands of a sessile organism. SIK1 does not merely transmit a linear growth signal; it actively quantifies and prioritizes inputs from development, immunity, and hormone pathways to inform the hub’s strategic decisions on resource allocation. Its output constitutes the primary processed intelligence on which the hub acts. A conserved kinase core with a plant-tuned allosteric switch. SIK1 retains the conserved kinase domain architecture of an active MAP4K (Zhang et al., 2018; Fig. 2A). Its activity is governed by a precise phosphorylation-dependent allosteric switch centered on Thr405 in the activation loop (A-loop). Computational structural biology reveals that Thr405 phosphorylation triggers the formation of a β-hairpin in the glycine-rich loop (G-loop), a rearrangement partly stabilized by a conserved salt bridge (Lys257-Glu254). This specific conformational change is the critical step that opens the catalytic pocket for substrate access (Mu et al., 2021; Fig. 2B). This switch is mediated by a network of essential residues (Lys278, Glu295, Arg370), which are highly conserved across STE20-like kinases. This suggests that the phosphorylation-dependent allosteric mechanism represents a family-wide regulatory logic that has been co-opted and precisely tuned in plants, forming the linchpin of SIK1’s integrator function to convert diverse upstream signals into a unified kinase activity state. Architectural innovation: Rewiring the interaction network. While its catalytic mechanism is conserved, SIK1’s interaction landscape is distinctly plant-shaped. It lacks canonical protein-interaction domains found in its orthologs, such as the CRIB/GBB motifs in yeast Ste20 or the SARAH domain in animal MST1/2 (Xiong et al., 2016; Fig. 2C). More significantly, it forges a direct, phosphorylation-dependent physical link with the scaffold protein MOB1A/B via its basic N-terminal region, bypassing the SAV1 scaffold obligatory in animal Hippo signaling. This novel interaction may exploit an evolutionarily conserved electrostatic logic. Intriguingly, this hypothesis is reminiscent of the electrostatic complementarity between the acidic surface of human MOB1 and the basic N-termini of its NDR kinase partners, suggesting a possible convergent evolutionary logic underlying specific MOB1-kinase partnerships (Fig. 2C). This streamlined, direct link is crucial for the rapid and faithful relay of integrated signals to the hub’s central processing module. Coordinating developmental programs: from organ growth to spatial patterning. For the hub to allocate resources strategically, it must first accurately assess the organism’s current developmental status and needs. As the primary integrator, SIK1 processes distinct yet interconnected developmental cues to guide both the quantitative investment in growth and its spatial organization, providing this essential situational awareness: • Quantifying growth via the JA pathway. SIK1’s role as a resource allocation hub is fundamentally demonstrated in its control of organ size—a direct metric of growth investment. Its strategic expression pattern, with lower levels in actively dividing tissues (e.g., root division zones) and higher accumulation in maturing tissues (e.g., vasculature, guard cells), hints at a function in the transition from proliferation to expansion. The sik1 mutant exhibits dramatic dwarfism, which cellular analysis traces to a defective cell division-to-expansion transition, manifesting as reduced cell number, size, and ploidy—hallmarks of delayed mitotic exit (Xiong et al., 2016; Galla et al., 2011; Pinosa et al., 2013). This phenotype reveals a profound evolutionary repurposing. While animal Hippo pathway mutants display overgrowth, the plant sik1 mutant shows inhibition—highlighting a radical rewiring of the module’s core logic toward growth restraint in a trade-off context (Wu et al., 2003). Mechanistically, SIK1 is a positive regulator of the jasmonate (JA) pathway, as the mutant represses key JA signaling genes (e.g., JAZ1/2/5/6/9/12, MYC2/3/4 ), linking it directly to JA-mediated growth inhibition and defense priming (Xiong et al., 2016; Fig. 3). Thus, through the JA pathway, SIK1 quantifies the “cost” of defense, generating a key variable for the hub’s strategic calculus. • Directing growth patterns via auxin signaling. Beyond setting the overall magnitude of growth, SIK1 also guides its spatial pattern by facilitating auxin-mediated non-cell-autonomous polarity. Mutations in SIK1 disrupt processes like root gravitropism and cotyledon development, and increase sensitivity to exogenous auxin (Zhang et al., 2021; Fig. 3). Transcriptomic profiling of sik1 mutants points to a mechanism involving the downregulation of auxin biosynthesis genes (e.g., TAR2, YUC2/4/6/8, GH3 ) and upregulation of ARF TFs. Intriguingly, this function appears independent of the canonical PIN-FORMED auxin efflux carriers, as their expression, localization, and turnover are unaffected in the mutant. This indicates that SIK1 regulates tissue polarity through a novel, PIN-independent node within the auxin signaling network, mapping the “where” for potential resource investment. • Integrated decision-making for development. Therefore, SIK1 does not merely promote or inhibit growth in a blanket fashion. It integrates the hormonal calculus of the growth-defense trade-off (via JA) with positional information governing tissue architecture (via auxin) (Fig. 3). This dual input allows the hub to make holistic decisions: not just whether to grow, but how much and in what spatial pattern to invest resources for optimal developmental outcomes. Serving as an immune hub to execute resource reallocation. When under biotic attack, the strategic equation shifts abruptly, demanding immediate resource reallocation. SIK1’s decision-making extends decisively into biotic stress responses, where it functions as a critical integration point within pattern-triggered immunity (PTI) (Couto & Zipfel, 2016). Its role here is dual: to potentiate immediate defense responses and to recalibrate the hormonal landscape, thereby directly enacting a resource trade-off. SIK1 is embedded in the core PTI machinery through multiple, specific interactions. It maintains immune readiness by regulating the stability of the central kinase BIK1, via phosphorylation at S236 and interaction with the extra-large G protein XLG2 (Zhang et al., 2018). Upon pathogen perception, this priming translates into cooperative action: SIK1 and BIK1 jointly drive the rapid extracellular reactive oxygen species (ROS) burst by fully activating the NADPH oxidase RBOHD. While BIK1 phosphorylates RBOHD, SIK1 directly phosphorylates the RBOHD N-terminus (S8, S9) as well as key activating residues S339 and S347 (Kadota et al., 2014; Yu et al., 2024; Fig. 3). Thus, SIK1 is an essential co-activator of a key defense output. Beyond activating acute responses, SIK1 simultaneously modulates the broader signaling context, evidenced in sik1 mutants which accumulate elevated salicylic acid (SA), exhibit reduced JA, and constitutively express the SA marker PR1 (Lal et al., 2018). Therefore, SIK1 acts as an immune signaling hub, coordinating 1) kinase stability (BIK1), 2) effector activation (RBOHD), and 3) hormone balance (SA/JA) to shape a coordinated early immune response (Fig. 3). Most importantly, this sophisticated immune activation comes at a direct cost to growth. SIK1-mediated defense actively suppresses plant development. This phenomenon is a clear manifestation of the hub’s core function: SIK1 integrates the pathogen threat signal and, through the very mechanisms described above, executes a strategic decision to reallocate finite cellular resources from growth programs to defense in real time. In summary, SIK1 is the quintessential upstream integrator of the plant Hippo hub. Through its conserved yet tunable kinase switch, its innovated direct partnership with MOB1, and its multifaceted regulation of JA, immune, and auxin pathways, SIK1 acts as the strategic gateway. It senses, weighs, and converts a multitude of internal and external signals into actionable inputs, enabling the hub to make informed decisions on where to allocate the plant’s finite resources for optimal fitness. MOB1: The Central Processor of the Plant Resource Allocation Hub The scaffold protein MOB1 is a conserved core component of the Hippo signaling pathway across eukaryotes (Citterio et al., 2005; Vitulo et al., 2007). In plants, however, MOB1 has evolved beyond a passive structural role. This chapter posits that MOB1 acts as the central processing unit (CPU) of the plant Hippo hub. It receives upstream signals (notably from SIK1), executes core cellular programs (cytokinesis, PCD), and, most critically, computes the hormonal balance between growth-promoting auxin and defense-associated jasmonate (JA). This integrative function allows MOB1 to directly quantify and implement strategic decisions on resource allocation, making it the master regulator of the growth-defense trade-off. A conserved scaffold with plant-tuned regulation. Plant MOB1 proteins are highly conserved in sequence, sharing over 80% amino acid identity among themselves, yet exhibit evolutionary specialization within plant-specific networks (Citterio et al., 2005, 2006). Critical functional motifs, such as the phosphorylation sites for upstream kinases (e.g., Thr12 and Thr35), are conserved and essential (Praskova et al., 2008; Cui et al., 2016). However, functional divergence is evident: alfalfa MOB1 cannot complement yeast mob1 mutants despite ~70% sequence identity, whereas Drosophila MOB1 (63% identity) can partially rescue Arabidopsis mutants, highlighting a rewiring of MOB1 function in plants (Citterio et al., 2006; Cui et al., 2016). Dynamic localization underpinning core cellular execution. The fundamental role of MOB1 is reflected in its cell cycle-dependent localization. In alfalfa, MOB1 localizes diffusely in the cytoplasm from G1 to S phases but condenses into punctate and fibrillary structures during G2 to M phase, associating with the preprophase band, spindle, and cell plate during cytokinesis (Citterio et al., 2005, 2006; Fig. 4A). This pattern is conserved in Arabidopsis, where MOB1 also localizes to the nucleus and cell division plane (Van Damme et al., 2004; Galla et al., 2011). Beyond cytokinesis, MOB1 is spatiotemporally linked to programmed cell death (PCD), with its accumulation coinciding with DNA fragmentation in degenerating reproductive cells (Citterio et al., 2005). Disrupting MOB1 function leads to aberrant PCD timing and sterility, demonstrating its role as a pivotal arbitrator between resource-consuming division and resource-recycling elimination (Galla et al., 2011; Fig.5). The functional dimer: AtMOB1A/B as a core heterocomplex. In Arabidopsis, the MOB1 family consists of four members, with AtMOB1A and AtMOB1B forming the primary functional unit. Although early models suggested non-redundancy due to expression differences (Pinosa et al., 2013), recent evidence reveals they are co-expressed, physically interact (as shown by co-immunoprecipitation and mass spectrometry), and preferentially form a potent heterodimer that is more stable and active than either homodimer (Guo et al., 2020; Fig.4B). Genetic analysis confirms this model: while mob1a single mutants show severe defects and mob1b mutants are nearly wild-type, the mob1a/b double mutant exhibits dramatically enhanced phenotypes (Guo et al., 2020). This establishes the AtMOB1A/B heterodimer as the dominant functional complex, analogous to mammalian MOB1A/B in tumor suppression (Nishio et al., 2012), and positions it as the core module for signal processing within the hub. The hormonal integrator: quantitatively balancing auxin-growth vs. JA-defense. MOB1’s function as the hub’s CPU is most critically defined by its role as a quantitative regulator of the auxin-JA hormonal nexus (Fig. 5). It acts as a central balancer that sets their relative amplitude, directly implementing the growth-defense trade-off decision. Promoting the growth axis: deep integration with auxin signaling. AtMOB1A’s role extends to a precise, mechanistic integration with the auxin machinery (Fig. 5). Genetic epistasis analyses place it in parallel or upstream of key AGC kinases (e.g., PID/WAGs) that phosphorylate PIN auxin efflux carriers. Higher-order mutants combining atmob1a with lesions in auxin biosynthesis or transport exhibit quintessential auxin-deficient syndromes (Cui et al., 2016). Molecularly, AtMOB1A fine-tunes the auxin response network by downregulating key AUXIN RESPONSE FACTOR genes ( ARF7, ARF19 ) (Cui et al., 2016). We propose that the MOB1 complex, potentially by scaffolding and activating a specific set of AGC kinases, serves as a plant-specific functional analog to YAP/TAZ, transducing Hippo hub signals into transcriptional reprogramming for growth. Suppressing the defense axis: a master repressor of JA signaling. Concurrently, the AtMOB1A/B heterodimer functions as a master transcriptional repressor of the JA pathway (Fig. 5). Loss of this repression in the mob1a/b double mutant unleashes a comprehensive JA hyper-response: elevated JA levels, hypersensitivity to exogenous MeJA, and sweeping upregulation of JA biosynthesis, signaling, and response genes (Huang et al., 2017). Crucially, the mechanistic link to growth arrest is established: elevated MYC2 directly represses the expression of PLT1/2 transcription factors, essential for root stem cell maintenance (Huang et al., 2017). This model is confirmed by the partial phenotypic rescue when MYC2 is mutated in the mob1a/b background. This MOB1-JA regulatory module has broad physiological relevance, also governing processes like pollen germination through interaction with MAP3Kε kinases (Mei et al., 2022). The core processing logic: the SIK1-MOB1 molecular rheostat. The antagonistic relationship between SIK1 and MOB1 within the JA pathway reveals the core computational algorithm of the hub. SIK1 acts as the upstream threat sensor and amplifier of JA-mediated defense, while the MOB1 complex functions as the essential downstream dampener, setting the basal threshold for JA signaling to permit growth. This creates a dynamic, homeostatic circuit. The genetic evidence is clear: despite their opposing effects on JA, the sik1 mob1a/b triple mutant shows more severe developmental defects than any single mutant, proving both components are non-redundant and converge on a common, essential pro-growth output (Fig. 5). We therefore propose the SIK1-MOB1 axis functions as a phosphorylation-dependent molecular rheostat. Its output—the balance between growth and defense—is determined by integrated signals (e.g., from MO25/FRY) that adjust its activity or composition, thereby modulating the sensitivity of the JA circuit to implement strategic resource allocation. In conclusion, plant MOB1 has evolved from a passive scaffold into the central processor of the resource allocation hub. By integrating upstream signals, executing core cellular programs, and directly computing the auxin-JA balance, it translates environmental and developmental cues into precise hormonal instructions. This allows the plant to dynamically allocate its finite resources. Future work must define the precise molecular mechanisms by which the SIK1-MOB1 rheostat is adjusted by environmental inputs and how its hormonal output directs specific transcriptional programs. A key challenge is to elucidate how this central processor is itself regulated by the very resource status it governs, closing the loop in the plant’s strategic decision-making system. 2.3 NDR: The Bimodal Kinase Executor at the Hub’s Command Interface The NDR kinase family represents the conserved, terminal effector module of the Hippo pathway across kingdoms (Tamaskovic et al., 2003; Hergovich et al., 2006). In plants, NDR kinases have evolved beyond their canonical role as serine/threonine kinases. This chapter posits that plant NDR kinases function as the hub’s primary bimodal executors. They are equipped with a unique dual-specificity phosphorylation capability (Ser/Thr and Tyr), which allows them to receive integrated commands from the upstream integrator complex and translate them into distinct, context-specific biochemical outputs—directly implementing the strategic decision to allocate resources toward either developmental programs or defensive responses. A conserved core with a plant-specific catalytic expansion. Phylogenetically, plant NDR kinases (e.g., RsNDR, PKL01, AtNDR1-8, TaAGC1) form a distinct clade within the AGC kinase family, separate from canonical members like PKA and PKC, and cluster with their fungal and mammalian orthologs, confirming deep evolutionary conservation (Imai et al., 2004;Tamaskovic et al., 2003; Hergovich et al., 2006). They retain the conserved twelve-subdomain kinase core and critical interactions, such as binding to the scaffold protein MOB1A/B, solidifying their position within the core Hippo module (Imai et al., 2004; Zhou et al., 2021). However, a pivotal biochemical innovation sets them apart: dual-specificity phosphorylation. Detailed studies of PKL01 (NDR kinase in Lotus japonicus ) revealed not only critical serine autophosphorylation (Ser317) but also tyrosine autophosphorylation (Tyr56), a capability extended to phosphorylating tyrosine residues in exogenous substrates (Kameshita et al., 2010; Katayama et al., 2012；Fig. 6). This dual-specificity was confirmed by LC-MS/MS identification of autophosphorylation sites and by experiments showing that dephosphorylated PKL01 could re-autophosphorylate on tyrosine in the presence of ATP, redefining plant NDRs from strict Ser/Thr kinases to versatile signaling interfaces capable of engaging with both Ser/Thr-dominated cascades (e.g., MAPK pathways) and tyrosine-influenced networks, dramatically expanding their regulatory bandwidth and precision in signal transduction. Executing developmental fidelity: ensuring reproductive investment ( Fig. 6 ). The NDR-MOB1 module is a non-redundant executor of reproductive development, a critical resource allocation priority. In Arabidopsis, NDR2/4/5 kinases are essential for pollen maturation and germination (Zermiani et al., 2015; Zhou et al., 2021). Their specific expression in late pollen and pollen tubes, and the phenotype of ndr2 ndr4 ndr5 mutants—featuring abnormal callose deposition, premature germination, and anther dehiscence defects during tricellular development—mirror the mob1a mob1b mutant phenotype. This genetic epistasis demonstrates that the NDR-MOB1 complex is the definitive output mechanism for a successful developmental program leading to reproduction. Embryonic lethality in higher-order ndr mutants, such as the ndr4 ndr6 ndr7 ndr8 quadruple mutant, further underscores their indispensable, cooperative role in foundational development (Yoon et al., 2021). Under favorable conditions, this module is actively deployed to secure reproductive success, a key strategic objective. Orchestrating stress adaptation: reallocating resources for survival ( Fig. 6 ). When environmental conditions deteriorate, the NDR module is repurposed to execute stress-adaptation programs, directly enacting a resource trade-off. In maize, a Hippo-like MOR network, including NDR/CBK1 homologs, is central to cold stress adaptation (Tian et al., 2023). Co-expression analyses linked this network to the central cold sensor COLD1 and known cold-response regulators, positioning it as a key transduction pathway. Cold stress dynamically regulates this module, upregulating an NDR-like kinase while downregulating a MOB-like protein. The increased cold sensitivity of NDR kinase mutants confirms its essential role as a positive executor of acclimation responses. Similarly, in wheat, the NDR kinase TaAGC1 acts as a key defense executor against Rhizoctonia cerealis (Zhu et al., 2015). Its upregulation in resistant and over-expression cultivars, and the demonstration that its activity enhances resistance by modulating ROS homeostasis and upregulating ROS-scavenging enzymes and defense gene expression, positions TaAGC1 as a direct implementer of immunity. In both cases, NDR kinase activity drives resource investment away from standard growth/reproduction and toward survival-oriented outputs. The bimodal executor: a molecular switch for priority-based decisions. We propose that the plant NDR-MOB1 module functions as a phosphorylation-based command interface (Fig. 6). Its activity and substrate specificity are likely modulated by upstream inputs from the integrative hub (e.g., via MOB1 phosphorylation status or partnering with specific MO25 paralogs). The kinase’s dual-specificity nature is crucial: it may phosphorylate distinct suites of substrates—development-specific TFs (e.g., VIP1) versus stress-responsive regulators—depending on the integrated signal received (Yoon et al., 2021). This allows a single conserved module to produce diametrically opposed physiological outcomes: driving pollen tube growth for reproduction or activating antioxidant systems for cold tolerance. It is not merely involved in parallel pathways; it is the final common biochemical executor that the hub uses to enforce its strategic decision. In summary, plant NDR kinases are the evolutionarily tuned execution arms of the Hippo resource allocation hub. Their conserved structure ensures fidelity within the pathway, while their acquired dual-specificity phosphorylation equips them with unprecedented versatility. By directly and differentially phosphorylating targets in developmental or stress-response pathways, the NDR-MOB1 complex translates the hub’s strategic assessments into concrete cellular actions, making it the definitive point where the decision to ”grow,” ”defend,” or ”reproduce” is biochemically implemented. Future research must define the precise upstream signals that toggle NDR’s output state and comprehensively map its context-dependent phospho-targets to fully decipher this central execution logic. 2.4 MO25: The Evolved and Programmable Platform for Signaling Diversification Positioned at the heart of the conserved GCK kinase network, the scaffold protein MO25 transcends its classical role as a mere kinase activator. In plants, it has evolved into a versatile and programmable platform that enabled the diversification of Hippo signaling. This chapter argues that lineage-specific gene duplication provided the raw genetic material, which natural selection shaped into specialized MO25 variants. These variants, through structural and expressional divergence, orchestrate the assembly of distinct signaling complexes, thereby facilitating the nuanced coordination of development and stress responses required for strategic resource allocation. An ancestral core repurposed for plant-specific partnerships. MO25 retains its fundamental, conserved function as a critical activator of Germinal Center Kinases (GCKs), binding to and potentiating kinases like the plant STE20-family members (Ferdaus & Delpire, 2025). This conserved mechanistic core ensures fidelity in kinase signaling. However, its interaction logic has been rewired for plant-specific networks. It integrates with key components of the plant Hippo (RAM/MOR) hub, such as SIK1 and NDR kinases, forming co-expression modules that govern fundamental processes like stem cell maintenance and organ polarity. This integration is supported by protein-protein interaction data showing that Arabidopsis MO25 physically associates with SIK1 and NDR kinases (Zermiani et al., 2015), positioning it not at the periphery, but as a central adaptor within the plant’s resource allocation circuitry. Gene duplication: The evolutionary substrate for functional innovation. A pivotal event in the evolution of plant MO25 function was a gene duplication at the dawn of land plants, giving rise to clades A and B (Bizotto et al., 2018). Subsequent divergence created a family of paralogs with distinct properties. In Arabidopsis, for example, one paralog (AtMO25-1) exhibits features of retroposition (intron-less, restricted expression), suggesting a possible origin via retroposition and adding a layer of dynamic evolution to this gene family (Bizotto et al., 2018). Critically, these paralogs diverged not only in expression patterns but also at key structural interfaces—including residues homologous to known kinase-binding sites. This divergence is not neutral; it represents the evolutionary programming of the MO25 platform, enabling it to engage with different client kinases or co-factors. We propose this functional diversification was a key innovation, allowing the ancestral Hippo/GCK module to expand its regulatory repertoire and address the unique signaling demands—such as meristem maintenance and stress negotiation—of sessile terrestrial life. Orchestrating development: From conserved proliferation to specialized patterning. The functional output of MO25 specialization is vividly demonstrated in plant development. Its role is deeply conserved at the cellular level but diversified in its organismal context. In moss ( Physcomitrium patens ), MO25A is essential for basic tip growth and stem cell division initiation (Ta et al., 2023). In rice, the osmo25a1 mutant fails in embryogenesis, with aborted shoot and root apical meristems and reduced mitosis, highlighting its non-redundant role in establishing the fundamental body plan (Ta et al., 2023). In Arabidopsis, MO25 proteins contribute to more sophisticated patterning, regulating stem cell dynamics and organ polarity in the shoot apical meristem. This progression from regulating basic cellular proliferation in early-diverging plants to coordinating complex tissue patterning in angiosperms illustrates how the duplicated and diversified MO25 platform was co-opted into increasingly elaborate developmental programs. A poised integrator for stress-mediated trade-offs: a compelling hypothesis. While direct evidence in plant immunity is still emerging, MO25’s strategic position makes it a prime candidate for coordinating growth-defense decisions. Given that: 1) its client GCK kinases are central to immune signaling in animals, 2) it physically integrates with the SIK1-MOB1 hub which directly executes immune resource reallocation, and 3) gene duplication often enables specialization in stress responses, a compelling hypothesis emerges. We propose that specific MO25 paralogs may function as stress-sensitive scaffolds, recruiting and activating immune-related GCK kinases upon pathogen perception. This would effectively reconfigure the Hippo hub’s output, shifting the balance from growth-promoting to defense-activating complexes. This model positions MO25 as a programmable switch within the trade-off machinery, a hypothesis that awaits testing through defining stress-induced changes in MO25 complex composition and by analyzing the phenotypic consequences of mutating specific MO25 paralogs under pathogen challenge. In conclusion, MO25 embodies the evolutionary innovation of the plant Hippo hub. From a conserved kinase activator, it has diversified into a family of specialized scaffolding platforms. Through gene duplication and divergence, MO25 proteins gained the capacity to assemble context-specific signaling complexes, thereby enabling the hub to precisely manage the multifarious demands of development and the inevitable stresses of terrestrial life. It is not just a static scaffold but an evolved and programmable node that increases the hub’s computational capacity for strategic resource allocation. Future work must decode the ”binding rules” of different MO25 paralogs and test their specific roles in enacting the critical trade-offs between growth, defense, and reproduction. 2.5 FRY: A Putative Molecular Processor for Strategic Trade-off Decisions Among the core components of the plant Hippo hub, the FRY protein remains enigmatic. In stark contrast to the well-characterized kinases and scaffolds, its function is largely inferred. However, its unique “sensor-executor” bimodal architecture and a growing network of indirect functional associations strongly suggest it is a potential, critical integration and transduction node within this signaling circuitry. This chapter argues that FRY likely acts as a molecular processor: it uses its ARM-repeat domain to converge inputs from growth, defense, and reproduction pathways and employs its predicted U-box E3 ubiquitin ligase activity to process and relay these signals, thereby executing specific molecular commands in strategic resource allocation. A built-in “sensor-executor” molecular architecture. The molecular structure of FRY provides fundamental clues to its predicted function. The Arabidopsis FRY protein belongs to the ARM-repeat superfamily (Gul et al., 2017). These repeats form a conserved superhelical armadillo fold—a versatile, multi-purpose interaction platform capable of encircling and binding diverse ligands. This structural motif is characteristic of integrators that receive inputs from multiple signaling pathways. More significantly, FRY is predicted to harbor a U-box domain, conferring E3 ubiquitin ligase activity (Mudgil et al., 2004). This “scaffold domain + catalytic domain” bimodal architecture is likely not incidental. It implies FRY can function not only as a hub (to “sense” and converge partners via ARM-repeats) but also as an effector (to “execute” ubiquitination modifications via the U-box), enabling direct biochemical processing and transduction of the converged signals. This design, fusing signal perception with immediate regulatory capacity, is the hallmark of a sophisticated integrator. A network of indirect evidence: a hub connecting the three trade-off dimensions. Although direct pathway mapping is lacking, studies across different systems sketch a broad connection between FRY and the three major life processes—growth, defense, and reproduction—supporting its hypothetical role as a central integrating node: • A regulator of growth and development: FRY was identified as a high-confidence candidate component within the FAMA complex, a transcriptional switch in stomatal development (Dolan & Chapple, 2018), directly linking it to the regulation of gas exchange critical for photosynthesis and water balance. Its co-expression with MED23, a subunit of the Mediator complex, further suggests a role in fine-tuning growth-related gene expression programs. • A potential Regulatory Valve in Stress Response: In tobacco, a FRY homolog was identified as a top-ranked early-warning biomarker during viral infection, with its expression markedly downregulated as disease progressed (Tarazona et al., 2019). Given the central role of ubiquitination in defense signaling (e.g., JA, ABA pathways), this downregulation could actively reprogram the host’s resource allocation strategy by altering the stability of key defense components (Dreher & Callis, 2007). • A putative player in reproduction: While direct evidence is absent, related ARM-repeat proteins have been shown to play key roles in floral identity, fertility, and pollen development, often by modulating small RNA silencing pathways (Li et al., 2024). Transcriptomic studies indicate that disrupting the function of such proteins affects pollen development pathways (Chen et al., 2023), implying FRY may play a redundant yet vital role in this critical reproductive phase. A central hypothesis: FRY as an environment-responsive molecular switch. Based on the above architecture and associations, we propose a unifying hypothesis: FRY is an environment-responsive molecular switch within the Hippo hub. Its operational logic may be as follows: when the plant perceives a specific signal (e.g., pathogen attack), the expression, localization, or activity of FRY is modulated, leading to specific changes in its ubiquitination pattern for different target proteins (which could be growth-promoting TFs or defense signaling components). For instance, in a defense mode, alterations in FRY activity or target specificity might simultaneously destabilize growth-promoting factors and activate defense proteins, thereby rapidly reallocating cellular resources from growth programs to immune responses. Its role in stomatal development and potential reproduction further consolidates its central position in deeper-level trade-offs involving water-use efficiency, carbon assimilation, and reproductive success. In summary, FRY is likely not a mere accessory protein but a key signal processor and execution unit within the plant Hippo hub. Its unique bimodal architecture empowers it to process multiplexed inputs and generate ubiquitination-based output instructions. Future research must experimentally validate whether FRY is a bona fide component of the Hippo pathway and employ proteomic approaches to systematically identify its interactors and ubiquitination targets under different physiological conditions. Deciphering how FRY receives upstream signals (e.g., whether regulated by SIK1 or MO25) and how its ubiquitination output precisely influences downstream effectors will be key to unraveling the mystery of how plants achieve intelligent resource allocation. In conclusion, we propose that the plant Hippo pathway constitutes a strategic hub for resource allocation, a paradigm that unifies its pleiotropic roles in development and stress responses. This evolutionary innovation is driven by specific adaptations in its core components: the direct SIK1-MOB1 sensor-processor axis that defines the central signaling corridor, the dual-specificity NDR kinase that serves as a versatile executor, and the diversified adaptor functions of MO25 and FRY. Together, these elements reconfigure a conserved kinase module into an integrated system capable of computing and executing the fundamental trade-offs between growth, defense, and reproduction. To advance this hub model from a conceptual framework to a predictive and actionable one, future research must address three interconnected frontiers: • B ridging the mechanism gap: from qualitative to quantitative. The foremost challenge is to quantify the dynamic signal flow through the hub. This requires moving beyond descriptive models to define the precise kinetics and stoichiometry of the core phosphorylation cascade. Key questions include understanding how diverse upstream cues are quantitatively integrated to modulate the activity of the SIK1 and MOB1 complexes, and elucidating the exact molecular mechanism—whether through competitive phosphorylation or regulated assembly of distinct complexes—that underlies their antagonistic regulation of the jasmonate pathway. Concurrently, applying structural biology to visualize plant-specific complexes, such as the SIK1-MOB1 heterodimer and potential FRY signalosomes, is essential to move from inference to mechanistic certainty. • Bridging the network integration gap: from module to system. A systems-level understanding necessitates mapping the hub’s interactions across the diverse cellular and temporal landscapes of the plant. Employing single-cell omics technologies will be crucial to resolve its interactome in specific contexts, such as the root stem cell niche or developing pollen. Furthermore, the hub’s role cannot be understood in isolation; its functional significance will be fully revealed only by exploring its crosstalk with other major signaling networks. For instance, investigating its interface with abiotic stress-sensing modules like the COLD1-associated MOR network in maize will test its potential as a central processor for multiple environmental signals. • Bridging the evolution and application gap: from knowledge to design. The pathway’s strategic logic offers a direct conduit from fundamental discovery to practical innovation. Evolutionary studies tracing how lineage-specific gene duplications (e.g., in the MO25 and NDR families) have driven functional diversification will provide insights into adaptive mechanisms. This knowledge, in turn, inspires novel strategies for crop improvement. Rational engineering approaches could focus on fine-tuning the SIK1-MOB1 rheostat to achieve an optimal balance between defense and yield, manipulating MOB1-mediated programmed cell death to improve hybrid seed systems, or leveraging FRY’s predicted role as a signal processor to build synthetic stress-resilience circuits. Deciphering the language of trade-offs encoded by this strategic hub will do more than answer a profound question in plant biology; it will provide the foundational principles for designing the productive, sustainable, and climate-resilient crops of the future . Acknowledgments This work was supported by the Innovation Team Foundation of State Key Laboratory of Ecological Safety and Sustainable Development in Arid Lands, China. Conflicts of Interest The authors declare no conflicts of interest. Data Availability Statement Data sharing is not applicable to this article as no new data were createdor analyzed in the study.

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This phosphorylation triggers complex assembly and autophosphorylation, ultimately leading to the phosphorylation and cytoplasmic retention of the transcriptional coactivator YKI by 14-3-3 proteins, thereby inhibiting its target gene expression (Wu et al., 2003; Harvey & Hariharan, 2012). A related Hippo-like variant in Drosophila uses FRY and TRC in place of SAV and WTS (Avruch et al., 2012). Mammals possess two parallel modules. The canonical Hippo pathway 1 is a GCK–NDR cascade linked by the scaffold proteins WWC1-3, which phosphorylates and inhibits the coactivators YAP/TAZ (Halder & Johnson, 2011; Avruch et al., 2012). Hippo pathway 2 employs MAP4Ks as upstream kinases, connects via NF2 without a WWC scaffold, and similarly inactivates YAP/TAZ but may direct distinct functional outputs (Zhong et al., 2023). In yeast, analogous systems include the MEN cascade and the RAM network. The MEN cascade involves CDC15 (GCK) phosphorylating DBF2 (NDR), scaffolded by NUD1/MOB1, to regulate mitotic exit by controlling the phosphatase CDC14 (Nelson et al., 2003). The RAM network, with KIC1 (GCK) and CBK1 (NDR) scaffolded by HYM1/MOB2 (and associated with SOG2 and TAO3), regulates ACE2 localization for cell separation (Baro et al., 2017). Plants are also thought to have two branches (Zermiani et al., 2015). One branch involves SIK1 (GCK) interacting with MO25-3, potentially signaling through FRY (a homolog of TAO3) to NDR-MOB1 to regulate meristem homeostasis and floral transition via the putative effector POL; SIK1 can also directly bind MOB1. The other branch involves MO25-1/4 and NDR kinases, which may govern pollen tube polarity by phosphorylating and regulating ROP-GEFs, activators of ROP GTPases. (Abbreviations: GCK, germinal center kinase; NDR, Dbf2-related kinase; TCoA, transcriptional coactivator; PP, phosphatase; TF, transcription factor; GEF, guanine nucleotide exchange factor.) Figure 2. Structural features and allosteric regulation of Arabidopsis SIK1: conservation and uniqueness. (A) Overview of the conserved kinase domain. The kinase domain of Arabidopsis SIK1 (residues 245–502) adopts the canonical fold of an active MAP4K (Zhang et al., 2018). Key conserved features are highlighted: the glycine-rich loop (G-loop, residues 253–264) containing the GXGXXG motif; the invariant catalytic Lys278 and Asp371; and the activation loop (A-loop, residues 398–408) with the DFG motif. Specific functional residues are labeled: Gly256, Gly258, Gly261 (regulatory site); Lys278 (ATP-binding); Asp371, Asp389 (catalytic site); Thr405 (phosphorylation site). (B) Allosteric activation by A-loop phosphorylation. Phosphorylation of Thr405 on the A-loop triggers allosteric activation (Mu et al., 2021). This induces the formation of a structured β-hairpin in the disordered G-loop, stabilized by a Lys257-Glu254 salt bridge, which opens the catalytic pocket. In the inactive, non-phosphorylated state, the disordered G-loop obstructs substrate access. Key residues (Lys278, Glu295, Arg370) form a communication network linking phospho-Thr405 to the conformational change in the G-loop (Mu et al., 2021). (C) Unique features defining SIK1 specificity. Arabidopsis SIK1 lacks canonical STE20-family interaction domains (e.g., CRIB, GBB, SARAH) found in its orthologs (Xiong et al., 2016). Instead, it engages MOB1A/B directly via its phosphorylated residues and N-terminal basic regions. This interaction is likely driven by electrostatic complementarity with the acidic surface of MOB1, representing a distinct mechanism from those observed in yeast, Drosophila, and mammalian orthologs. Figure 3. Integrated Decision-Making and Resource Trade-Offs by SIK1 in Development and Immunity. SIK1 functions as a central signaling hub that integrates developmental and immune cues to strategically allocate cellular resources. During development, it coordinates hormonal signaling to quantify and guide growth. On one hand, SIK1 acts as a positive regulator of the jasmonate (JA) pathway, modulating the expression of key JA signaling genes (e.g., JAZ1/2/5/6/9, MYC2/3/4 ) to quantify growth investment (Xiong et al., 2016). This allows SIK1 to assess the “cost” of defense, providing a critical parameter for resource allocation. On the other hand, it regulates auxin signaling through a novel, PIN-independent node, influencing the expression of auxin biosynthesis genes (e.g., TAR2, YUC2/4/6/8 ) and ARF transcription factors, thereby directing spatial growth patterning in processes such as root gravitropism and cotyledon development (Zhang et al., 2021). Upon biotic stress, SIK1 transitions to an immune signaling hub, executing real-time resource reallocation. It maintains immune readiness by phosphorylating the core kinase BIK1 at Ser236 and interacting with it (Zhang et al., 2018). During pattern-triggered immunity, SIK1 cooperates with BIK1 to fully activate the NADPH oxidase RBOHD: SIK1 directly phosphorylates RBOHD at its N-terminus (Ser8, Ser9) and at Ser339/Ser347, which is essential for driving the rapid ROS burst (Kadota et al., 2014; Yu et al., 2024). Simultaneously, SIK1 is crucial for balancing the salicylic acid (SA) and JA pathways, as its loss of function leads to SA accumulation, reduced JA, and constitutive expression of the SA marker gene PR1 (Lal et al., 2018). This immune activation directly suppresses growth, demonstrating SIK1’s role in dynamically arbitrating the growth–defense trade-off by transitioning from a developmental assessor to an immune executor that reallocates resources in real time (Couto & Zipfel, 2016). Figure 4. Subcellular dynamics and functional heterodimerization of MOB1 proteins. (A) Cell cycle-dependent localization of MOB1. In alfalfa, MOB1 localizes diffusely in the cytoplasm during G1 to S phases but condenses into punctate and fibrillary structures from G2 to M phase. It associates with the preprophase band, spindle microtubules, and the cell plate during cytokinesis (Citterio et al., 2005, 2006). (B) The AtMOB1A/B heterodimer constitutes the core functional complex in Arabidopsis . AtMOB1A and AtMOB1B exhibit overlapping expression patterns and physically interact to form a heterodimer, as demonstrated by co-immunoprecipitation, IP-mass spectrometry, and luciferase complementation imaging (Guo et al., 2020). This heterodimer is more stable and active than the respective homodimers. Genetic analyses support this model, where mob1a/b double mutants show synergistic defects compared to single mutants, indicating that the AtMOB1A/B heterodimer is the primary functional unit with partial redundancy (Guo et al., 2020). Figure 5. The Hippo signaling hub in Arabidopsis : MOB1 function and SIK1-MOB1 crosstalk in resource allocation. MOB1 integrates signaling across development, stress, and reproduction. In development, MOB1 promotes cell proliferation and expansion by positively regulating the auxin pathway and suppressing the jasmonate (JA) pathway (Cui et al., 2016; Huang et al., 2017). Its expression is induced by abiotic stresses (e.g., nitrogen starvation), biotic stresses (e.g., P. syringae infection), and hormones (e.g., ABA, SA). In reproduction, MOB1 facilitates programmed cell death (PCD) for anther tapetum degeneration and functional megaspore specification; its disruption causes sterility (Citterio et al., 2005; Galla et al., 2011). MOB1 also prevents premature pollen germination by interacting with MAP3Kεs and repressing JA signaling (Mei et al., 2022). Furthermore, MOB1 is essential for embryogenesis, with mob1a mutants exhibiting severe division defects (Galla et al., 2011). Genetic interaction between SIK1 and MOB1 in auxin and JA signaling. The SIK1-MOB1 module acts synergistically as positive regulators of the auxin pathway (green); loss-of-function mutants display auxin-deficient dwarfism (Cui et al., 2016). Conversely, they function antagonistically in the JA pathway (blue): SIK1 promotes while the MOB1A/B heterodimer suppresses JA signaling (Xiong et al., 2016; Huang et al., 2017). This is evidenced by the sik1 mutant (reduced JA, enhanced SA) and mob1a/b mutants (JA hyperaccumulation and hypersensitivity). The enhanced severity of the sik1 mob1a/b triple mutant underscores their non-redundant, convergent role in promoting growth. (Abbreviations: DEGs, differentially expressed genes; JA, jasmonic acid; SA, salicylic acid; ABA, abscisic acid; PCD, programmed cell death.) Fig. 6. NDR kinase acts as a dual-specificity, bimodal executor for resource allocation decisions. LC‑MS/MS and functional assays confirm that plant NDR kinases are dual‑specificity kinases (Kameshita et al., 2010; Katayama et al., 2012). As demonstrated in PKL01, this capability encompasses autophosphorylation on both Ser317 and Tyr56, phosphorylation of tyrosine in exogenous substrates, and the key functional property of re‑autophosphorylation on tyrosine by dephosphorylated PKL01 in the presence of ATP. This redefines plant NDRs as versatile signaling interfaces that integrate both Ser/Thr‑ and tyrosine‑based networks, moving beyond the conventional scope of Ser/Thr kinases. The NDR-MOB1 module functions as a dedicated executor in two critical resource-allocation contexts. Under normal conditions, it ensures reproductive fidelity: in Arabidopsis, NDR2/4/5 kinases are essential for pollen maturation and germination; their loss leads to abnormal callose deposition, premature germination, and anther dehiscence defects, phenocopying MOB1 mutants (Zermiani et al., 2015; Zhou et al., 2021). Under stress, the module is repurposed for survival. In maize, cold stress dynamically regulates an NDR-containing Hippo-like network through the sensor COLD1 and Hippo member TAO3/FRY; loss of the NDR kinase abolishes acclimation, confirming its positive executor role (Tian et al., 2023). In wheat, the NDR kinase TaAGC1 is upregulated in resistant cultivars. Its overexpression enhances resistance to Rhizoctonia cerealis by modulating ROS homeostasis and defense gene expression (Zhu et al., 2015). Thus, this complex directly implements the organism’s priority switch between reproductive investment and stress survival. (Abbreviation: LC-MS/MS, liquid chromatography–tandem mass spectrometry; GP, germ pore; PT, pollen tube; Y2H, yeast two-hybrid; BiFC, bimolecular fluorescence complementation; Co-IP, co-immunoprecipitation; OE, overexpression) Fig. 7. The plant Hippo pathway as a strategic hub for resource allocation: a unified model and future directions. We propose that the plant Hippo pathway functions as an evolutionarily shaped strategic hub, computing the fundamental trade-offs between growth, defense, and reproduction. This model unifies its pleiotropic roles through specific adaptations in its core components: the direct SIK1-MOB1 sensor-processor axis, the dual-specificity NDR kinase as a versatile executor, and the diversified adaptor functions of MO25 and FRY. To advance this framework into a predictive system, future research must focus on three interconnected frontiers: (1) Quantitatively dissecting the core mechanism , by precisely measuring signaling flux kinetics using approaches such as quantitative phosphoproteomics, and resolving the structural basis and molecular logic underlying processes like the antagonistic regulation of the jasmonate pathway; (2) Mapping the systems-level interactome , by employing technologies like single-cell omics to reveal the hub’s context-specific interaction networks across different cell types and developmental stages, and elucidating its crosstalk with other major signaling systems, such as COLD1-mediated stress sensing; (3) Driving design-led application, by tracing the evolutionary expansion of gene families like MO25 to understand the principles of functional diversification, and leveraging this knowledge for rational design—such as fine-tuning SIK1-MOB1 signaling amplitude or engineering synthetic resilience circuits—to develop crops with optimized traits. 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Authors Metrics & Citations Metrics Article Usage 261views 109downloads Citations Download citation Yulan Shi, Li-Zhe An, Xian Xue. The Plant Hippo Pathway: An Evolved Hub for Strategic Resource Allocation Governing Growth-Defense-Reproduction Trade-offs. Authorea. 27 December 2025. DOI: https://doi.org/10.22541/au.176680835.51863891/v1 DOI: https://doi.org/10.22541/au.176680835.51863891/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.