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Published in final edited form as: Curr Opin Cell Biol. 2025 Jun 3;95:102544. doi: 10.1016/j.ceb.2025.102544

RAS/ERK signaling and PLK1: Coordinating Developmental Regulation and Disease Mechanisms

Han Bit Baek 1,2, Swathi Arur 1,2,*
PMCID: PMC13431139  NIHMSID: NIHMS2197184  PMID: 40466213

Abstract

The RAS/ERK signaling pathway is a critical regulator of cellular processes such as proliferation, differentiation, and survival – core mechanisms that drive development. Dysregulation of RAS/ERK signaling is implicated in developmental disorders, including RASopathies, as well as in various cancers. Polo-like kinase 1 (PLK1) is a crucial orchestrator of both meiotic and mitotic cell cycle and plays an equally important role in development. Notably, abnormal ERK signaling can produce phenotypes that closely resemble those caused by PLK1 deficiency, suggesting a functional intersection between these pathways. In this review, we explore the emerging links between RAS/ERK and PLK1 signaling during development and highlight the broad range of biological processes potentially governed by their interaction.

Since the discovery of germ cells, scientists have sought to understand how a fertilized oocyte gives rise to the vast diversity of cell types in the body. Over time, it became clear that cell signaling – the process by which cells communicate internally and with each other – is essential for cell proliferation, fate specification, and coordination of tissue formation [1]. These pathways typically begin with the interaction of extracellular ligands and membrane receptors, triggering intracellular cascades that alter cellular metabolism, gene expression, and/or cytoskeletal networks that guide key developmental events [1].

RAS/ERK signaling

One of the most critical pathways in cell signaling is the RAS/ERK signaling pathway, which regulates development, cell proliferation, and survival [2]. RAS (Rat sarcoma) is a small GTPase that activates a downstream kinase cascade, culminating in the activation of ERK (Extracellular signal-regulated kinase), the terminal kinase in the pathway [2] (Figure 1). Activated ERK phosphorylates numerous substrates, regulating diverse cellular processes [2]. Dysregulation of this pathway can lead to oncogenic transformation, tumor formation, and metastases [2,3]. Developmentally, dysregulation of RAS/ERK signaling causes a spectrum of disorders called RASopathies, characterized by short stature, craniofacial abnormalities, heart malformations, and intellectual disability [4].

Figure 1. The RAS/ERK signaling pathway.

Figure 1.

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The RAS/ERK signaling pathway is initiated when an extracellular ligand binds to a receptor tyrosine kinase (RTK). This causes the RTK to dimerize and the two RTKs phosphorylate each other. The phosphorylated tyrosine residues serve as docking sites for the adaptor proteins, GRB2 and SHP2. They in turn recruit SOS, a guanine nucleotide exchange factor (GEF). SOS activates the small GTPase, RAS, which in turn recruits and activates RAF. RAF is a kinase that phosphorylates and activates MEK. MEK is another kinase that phosphorylates and activates ERK. ERK is the terminal kinase in this core pathway that phosphorylates and thereby regulates its cytoplasmic and nuclear effectors (orange).

RAS/ERK signaling was first elucidated in developmental systems such as Drosophila, and C. elegans, where it controls the fate of photoreceptors [5] and vulval cells [6], respectively. Typically, ERK promotes fate decisions through phosphorylation of transcription factors that alter gene expression [2]. However, evolving work over the last decade or so show that ERK also regulates tissue maintenance and differentiation such as maintenance of oocyte production in the C. elegans gonad. In C. elegans, ERK activity is required for proper oogenesis; without it, germ cells fail to differentiate into oocytes [7]. Conversely, premature ERK activation accelerates oocyte formation, but reduces oocyte quality and increases embryonic lethality [8].

Importantly, this regulatory role of ERK in oogenesis is conserved across species [9]. In Drosophila [10], zebrafish [11], and mice [12,13], ERK is similarly activated during oocyte development and is essential for female fertility [14,15]. However, a striking conserved feature is that ERK is inactivated during the oocyte-to-embryo transition, though the exact timing of inactivation varies depending on the species: ERK is inactivated following egg activation in flies [10] and after metaphase II arrest in zebrafish and mice [11–13]. This conserved inactivation suggests that persistent ERK at the oocyte-to-embryo transition is detrimental to early embryonic development. This is intriguing to consider since ERK promotes proliferation [2], which is important for developing embryos. Thus, while ERK promotes proliferation, its inactivation may be necessary for proper zygotic development. It is possible that ERK needs to be inactivated for the earliest events of zygotic formation because presence of ERK signaling poisons cellular dynamics during the oocyte-to-embryo transition, and that it is reactivated following zygotic genome activation to regulate transcription factors and mediate embryonic development. A recent study in C. elegans [16] found that ectopic ERK activity in fertilized oocytes disrupts nuclear envelope dynamics by phosphorylating and inhibiting Polo-like kinase 1 (PLK-1), a kinase essential for nuclear envelope breakdown and cytokinesis [17–21]. These findings underscore the need for precise temporal control of ERK signaling at the oocyte-to-embryo transition.

Consequences of aberrant ERK signaling during oocyte-to-embryo transition

In C. elegans, ERK is active in the prophase I arrested oocytes [22], and inactivates as oocytes progress to metaphase I and beyond [22,23]. In animals carrying a gain-of-function RAS mutation [24] (L19F mutation in the RAS GTPase or RAS(act)), ERK remains ectopically activated in metaphase I and II oocytes [16]. This aberrant activation allows detailed investigation into the consequences of persistent ERK signaling during the oocyte-to-embryo transition.

In these RAS(act) mutant animals, oocytes frequently exhibit polar body defects, indicating impaired meiotic divisions, reduced oocyte quality, and lower fertility [16]. Interestingly however, many oocytes from these mutant animals appear morphologically normal, yet the resulting embryos are abnormal: they are smaller, with shortened anterior-posterior axis, resulting in a more spherical shape [16]. Additionally, the embryonic blastomeres often contain multiple nuclei, indicating defects in mitosis [16]. Collectively, these observations suggest that ectopic ERK activity in oocytes interferes with early embryonic cell division, supporting a model in which developmental disorders such as RASopathies may originate from aberrant ERK activation in the oocyte.

This model is reinforced by findings in other organisms. In zebrafish, embryos carrying a SHP2 D61G mutation that hyperactivates RAS/ERK signaling initially elongate their anterior-posterior axis but later undergo axis shortening [25]. In mice, homozygous HRAS G12V strongly activates ERK and is lethal while heterozygous HRAS G12V mice are smaller with craniofacial abnormalities and reduced muscle mass and subcutaneous fat [26]. Together, these studies highlight a common theme: ERK must be tightly regulated during the oocyte-to-embryo transition to ensure developmental competence. Its precise inactivation appears to be a conserved and essential feature of successful embryogenesis across species.

Role of Polo-like kinase 1 in mitosis and meiosis

PLK1 is a conserved serine/threonine kinase that plays a central role in regulating both mitosis and meiosis [27]. Structurally, it has an N-terminal kinase domain responsible for its catalytic activity and a C-terminal polo-box domain (PBD), which mediates substrate recognition and localization [28]. PLK1 orchestrates nearly every stage of cell division, including mitotic entry [29], nuclear envelope breakdown (NEBD) [16–20], centrosome maturation [30], spindle formation [31], chromosome alignment and segregation [32,33], and cytokinesis [21]. Consequently, PLK1 depletion or inhibition in embryos results in severe mitotic defects, such as multinucleated cells and developmental arrest of the embryo [16,21]. In addition to its mitotic functions, PLK1 also plays a critical role in regulating meiotic division in oocytes [27]. It regulates meiotic spindle assembly, NEBD, chromosomal alignment and segregation, and polar body extrusion [34,35]. Therefore, dysregulation of PLK1 function can compromise oocyte quality, developmental competence, and reduce overall fertility.

Regulation of PLK1

Given PLK1’s involvement in numerous vital cellular processes, its activity is tightly regulated throughout space and time. PLK1 is controlled through multiple mechanisms to ensure precise coordination of its abundance, activity, and subcellular localization throughout the cell cycle [36]. These mechanisms include transcriptional regulation, post-translational modifications, and protein-protein interactions. Transcriptionally, PLK1 expression is coordinated with cell cycle progression. Complexes such as the DREAM and MuvB-FOXM1 complexes repress PLK1 during interphase and activate its expression during mitosis [36]. Proteolytically, PLK1 abundance is regulated by ubiquitin-mediated degradation. During anaphase, the APC/C complex targets PLK1 via its RXXL D-box motif at Arg337, marking it for proteasomal degradation [37] (Figure 2A).

Figure 2. Post-translation modifications regulate PLK1.

Figure 2.

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(A) Diagram of human PLK1 domains with post-translational modifications. The letters and numbers above the diagram mark the modified amino acid. The kinase domain T-loop is demarcated by the darker gray box. Phosphorylation sites are marked in blue and ubiquitination sites are marked in pink. The known kinases and E3 ubiquitin ligases that perform the respective post-translational modifications are listed below. PB1 = polo-box 1. PB2 = polo-box 2. Together, the PB1 and PB2 create the polo-box domain (PBD) that can bind to other proteins.

(B) Diagram of C. elegans PLK-1 domains with post-translational modifications. The letters and numbers above the diagram mark the modified amino acid. The kinase domain T-loop is demarcated by the darker gray box. Phosphorylation sites are marked in blue. The T198 phosphorylation site within the T-loop has also been shown to be phosphorylated by CDK1 in yeast(*).

PLK1 is also subject to activating phosphorylations particularly at Thr210 within its T-loop – a conserved motif within the kinase domain essential for catalytic activity [36]. This residue is phosphorylated by Aurora A and Aurora B during the G2 and M phases to promote mitotic entry, chromosome alignment, and chromosome segregation [28] (Figure 2A). In budding yeast, PLK1 homolog Cdc5 is similarly activated through CDK1 (CDC28 in yeast)-mediated phosphorylation at Thr242 (analogous to human PLK1 Thr214) [38] (Figure 2B). In C. elegans, ERK phosphorylates the homologous residue Thr198 on PLK-1 [16] (Figure 2B). Additionally, sites such as Ser137, phosphorylated by CHK1, are also critical for PLK1 activation in the context of DNA damage repair [39] (Figure 2A). Thus, multiple kinases phosphorylate key sites within PLK1 in different contexts to regulate enzyme activity.

Beyond regulation of PLK1 activity, PLK1 localization is dynamically regulated via phosphorylation-dependent substrate binding. The PBD domain recognizes phosphorylated Ser/Thr motifs, especially those primed by proline-directed kinases like CDK1 [36]. For example, in C. elegans, phosphorylation of nuclear pore proteins, NPP-1 and NPP-11, by CDK-1 recruits PLK-1 to the nuclear envelope [18]. Non-proteolytic ubiquitination also plays a role: CUL3–KLHL22-mediated ubiquitination of PLK1 at Lys492 promotes its dissociation from kinetochores [40] (Figure 2A). PLK1 thus exhibits dynamic localization patterns – during interphase it is distributed across the cytoplasm, microtubules, and centrosomes [36]; during mitosis it also localizes to the nucleus, kinetochores, central spindle, and the midbody [18,36]. These spatiotemporal changes are tightly controlled by the combined action of kinases and ubiquitin ligases to ensure precise cell division.

PLK1 in oogenesis

While Plk1 is best known for its mitotic roles, it is also an essential regulator of meiotic events. Because complete knockout of Plk1 is embryonic lethal, conditional knockout approaches have been used to study its function during oogenesis. In mice, specific deletion of Plk1 using the Spo-11-Cre driver leads to absence of PLK1 in metaphase I oocytes [41]. These oocytes fail to transition from metaphase to anaphase during meiosis I and do not extrude the first polar body [41]. Furthermore, ~ 40% of these Plk1-deficient oocytes exhibit abnormal chromosome compaction, where bivalents (paired homologous chromosomes) appear as diffuse chromatin instead of tightly condensed chromosomes [41]. Another 40% fail to form bipolar spindles, and those that do, exhibit shorter and abnormally wider spindles [41]. These defects in chromosome architecture and spindle assembly, likely underlie the meiotic arrest and infertility observed in these animals. Similar findings have been observed in C. elegans, where acute inhibition of an analog-sensitive PLK-1 allele disrupts chromosome alignment and spindle assembly, completely blocking polar body extrusion during meiosis I [35]. These results highlight the evolutionarily conserved role of PLK1 in coordinating meiotic events essential for oocyte maturation.

PLK1 in embryogenesis

Beyond oogenesis, Plk1 is indispensable for embryonic mitotic divisions. Crosses between heterozygous Plk1 knockout mice Plk1(+/−) yield no viable homozygous Plk1(−/−) offspring [42], underscoring the essential nature of this kinase to early embryonic viability. Plk1 null embryos arrest before the morula stage with 42% showing prometaphase-like defects including misaligned chromosomes and a failure to progress to anaphase or telophase [42]. Immunofluorescence analysis revealed spindle defects, including monopolar and multipolar spindle in 35% and 13% of embryos, respectively. Some cells also exhibited polyploid nuclei, suggesting cytokinesis failure contributes to embryonic lethality [42]. Altogether, these defects demonstrate that Plk1 plays a key role in the establishment of proper chromosome alignment and segregation as well as formation of the bipolar spindle. While mitosis can initiate in Plk1 null embryos, the absence of Plk1 leads to defects in mitotic progression, and the accumulation of mitotic defects leads to developmental arrest and embryonic lethality [42].

In C. elegans, PLK-1 function is essential even earlier. Inhibition of an analogue sensitive PLK-1 allele (C52V and L115G) using the ATP analog 1NM-PP1 impairs cytokinesis in one-cell embryos, where furrow formation initiates but fails to complete [21]. In embryos carrying a temperature sensitive plk-1(or683ts) allele (M547K mutation), paired nuclei are observed in two-cell embryos, indicating a failure in pronuclear fusion following fertilization [17]. These defects reveal that PLK-1 plays a critical role in early zygotic development, ensuring proper chromosome segregation, spindle dynamics, cytokinesis and nuclear integrity [16–21,32,42]. Together, these findings establish PLK1 as a master regulator of cell division. Its functions span meiosis and mitosis, from oocyte formation to early embryogenesis, and its activity must be precisely coordinated through complex layers of regulation. Disruption of PLK1 can lead to profound defects in fertility and embryonic viability across species.

Nuclear envelope breakdown is a multi-step process

The nucleus is a membrane-bound organelle that houses and protects the eukaryotic genome [43]. Its structural integrity is critical: nuclear abnormalities can disrupt genomic integrity and/or gene expression leading to a wide range of diseases and developmental disorders [43]. The nucleus achieves this protective role by physically separating the nucleoplasm – containing chromosomes and nuclear proteins – from the cytoplasm. This separation is mediated by the nuclear envelope, a specialized extension of the endoplasmic reticulum (ER) composed of two tightly apposed lipid bilayers [44,45] (Figure 3). Embedded within these bilayers are nuclear pore complexes (NPCs) – large protein assemblies that gate off the exchange of macromolecules between the nucleus and the cytoplasm [46] (Figure 3). These complexes restrict the passive diffusion of molecules larger than ~ 40kDa, ensuring selective transport [46] (Figure 3). Beneath the inner membrane lies the nuclear lamina, a fibrous network of lamin proteins that provide mechanical support and maintain nuclear shape [46] (Figure 3). The nuclear lamina also plays a role in genome organization by anchoring chromatin at Lamina-associated domains (LADs) [47].

Figure 3. Nuclear envelope breakdown is a multi-step process.

Figure 3.

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The nuclear envelope includes the nuclear membrane (purple), which is an extension of the endoplasmic reticulum, and the nuclear lamina (blue). During open mitosis, NEBD occurs in three main phases. First, the nuclear pore complexes (NPCs) disassemble, permeabilizing the nuclear envelope. This allows kinases to enter the nucleus, and they phosphorylate the nuclear lamina, leading to its depolymerization. Depolymerization of the nuclear lamina releases its hold on the nuclear membrane, allowing them to retract into the ER.

Because of this structural complexity, nuclear envelope breakdown (NEBD) is a highly coordinated multi-step process that is essential for cell division. NEBD begins with disassembly of NPCs, which opens ~ 80 nm gaps in the nuclear envelope, allowing cytoplasmic components – including mitotic kinases – to access nuclear contents [45,46] (Figure 3). This is followed by depolymerization of the nuclear lamina, releasing chromatin from the nuclear periphery [45] (Figure 3). Finally, the nuclear membranes retract into the ER, completing NEBD and enabling spindles to access chromosomes [45] (Figure 3).

PLK-1 is required for merging parental genomes in C. elegans embryos

In the C. elegans one-cell embryo, proper development depends on the fusion of the maternal and paternal pronucleus – a process that establishes the diploid zygotic genome [16–19]. In most metazoans, this genome fusion requires NEBD at the site where the two pronuclei meet [48]. In C. elegans, this localized NEBD is driven by the coordinated action of CDK-1 and PLK-1, two essential mitotic kinases [17–19]. While CDK-1 and PLK-1 both regulate NEBD, PLK-1 has a broader role in C. elegans than in other systems, extending beyond NPC disassembly to include lamina breakdown [19,49]. When PLK-1 is inhibited or depleted in one-cell embryos, NEBD fails, and the maternal and paternal genomes remain in separate nuclear compartments, resulting in “paired nuclei” in the two-cell embryo [17–19]. These findings establish PLK-1 as a key regulator of multiple steps in NEBD and demonstrate its essential role in pronuclear fusion and early embryonic development in C. elegans.

ERK regulates PLK-1 to control nuclear dynamics in C. elegans embryos

The convergence of ERK and PLK-1 signaling pathways in controlling nuclear events during early development reveals a critical regulatory axis with broad implications. Both kinases are known to regulate key aspects of meiosis and mitosis, and disruptions in either pathway result in similar developmental phenotypes. Their intersection suggests coordinated regulation of shared cellular processes. PLK1 is known to be activated by multiple kinases – Aurora A [50], Aurora B [51], CDK1 [29,38], and CHK1 [39] – that modulate its activity, localization, and substrate interactions via phosphorylation. A recent finding adds ERK to this list, showing that ERK can phosphorylate and inhibit PLK-1 in the developmental context of NEBD during early embryonic development [16]. This represents a novel mode of PLK-1 regulation and reveals how misregulated ERK activity can poison early development. Following fertilization in C. elegans, the maternal and paternal pronuclei must break down their nuclear envelopes at the site of contact to merge their genomes. PLK-1 facilitates this localized NEBD, enabling pronuclear fusion and diploid zygote formation [16–20]. However, ectopic activation of ERK in the one-cell embryo leads to phosphorylation of PLK-1 at Ser404, which interferes with this process [16] (Figure 2B). The nuclear envelope persists between the two pronuclei, preventing genome fusion and resulting in paired nuclei and embryonic lethality [16]. These findings underscore the importance of ERK inactivation at the oocyte-to-embryo transition and reveal a novel ERK-PLK-1 signaling axis that governs nuclear remodeling. Given the conserved roles of both kinases, this regulatory mechanism may apply broadly across species and cell types.

Conclusion

The RAS/ERK signaling pathway is a central regulator of diverse cellular processes, from proliferation and differentiation to survival and development [2]. Misregulation of this pathway is a well-established driver of oncogenesis [2,3]. Furthermore, RAS/ERK signaling also plays key roles in germ cell development [7–9,22] with ectopic signaling leading to birth defects such as RASopathies [4]. Similarly, PLK-1 is a master regulator of both mitotic and meiotic processes, and its function is essential for genome stability and fertility [27,28,36]. The discovery that ERK directly inhibits PLK-1 during control of nuclear envelope dynamics in C. elegans embryos provides a new insight into how these pathways intersect. Their interaction may explain how misregulation of ERK signaling, as observed in disorders such as RASopathies, disrupts early developmental processes. Because ERK and PLK-1 are highly conserved, further investigation into their crosstalk could reveal fundamental principles of developmental signaling, genome organization, and cell cycle control.

Acknowledgements

The authors thank all members of the Arur lab for helpful discussions. Work in the Arur Lab is funded by National Institutes for Health R35 GM140933 and R01 HD101269 to SA.

Footnotes

Conflict of Interest

The authors declare no conflict of interest.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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