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Event: 2245
Key Event Title
Altered Cell Differentiation Signaling
Short name
Biological Context
Level of Biological Organization |
---|
Molecular |
Cell term
Organ term
Key Event Components
Process | Object | Action |
---|---|---|
cell differentiation | abnormal | |
cell surface receptor signaling pathway | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
Deposition of energy leading to bone loss | KeyEvent | Vinita Chauhan (send email) | Open for citation & comment | Under Review |
Taxonomic Applicability
Life Stages
Life stage | Evidence |
---|---|
All life stages | Moderate |
Sex Applicability
Term | Evidence |
---|---|
Unspecific | Low |
Key Event Description
Cell differentiation pathways are the processes through which unspecialized cells, such as stem cells, develop into specialized cells with distinct functions (Soumelis and Liu, 2006). These pathways are tightly regulated by a complex interplay of signaling molecules and their receptors, the binding dynamics of transcription factors, and epigenetic modifications. Signaling molecules like growth factors and cytokines bind to cell surface receptors, triggering intracellular cascades that activate specific transcription factors. Transcription factors regulate dynamically during cell differentiation, they can be classified as static, dynamic, enhanced and suppressed states. These transcription factors then bind to DNA, regulating the expression of genes necessary for the specialized function of the cell. Epigenetic modifications, such as DNA methylation and histone modification, further ensure that the gene expression patterns are stably maintained over cell divisions (Tanabe, 2015).
Disruptions in cell differentiation pathways can occur due to various mechanisms, including genetic mutations, epigenetic alterations, and environmental factors. Mutations in genes encoding signaling molecules, receptors, or transcription factors can lead to aberrant activation or suppression of these pathways, preventing proper cell differentiation. Epigenetic alterations, such as aberrant DNA methylation or histone modification patterns, can also result in inappropriate gene expression, further hindering the differentiation process (Miller and Grant, 2013). Environmental factors, including exposure to toxins, radiation, or pathogens, can induce oxidative stress or DNA damage, leading to the activation of stress response pathways that interfere with normal differentiation. Persistent activation or inhibition of these pathways can lead to aberrant cell fate decisions (Kharrazian, 2021). These disruptions can have significant consequences, contributing to developmental disorders, cancer, and other diseases (Wu et al., 2023).
Key Differentiation Pathways: Description and Components for Measurement
WNT/β-Catenin Pathway:
The WNT/β-Catenin pathway plays a role in regulating the differentiation of various cell types by controlling gene expression. It is crucial for embryonic development, tissue homeostasis, and stem cell maintenance (Clevers et al., 2014). In particular, WNT signalling regulates bone cell homeostasis, and activation of this pathway results in increased bone mass and strength (Baron and Kneissel, 2013). The pathway is activated by WNT proteins binding to Frizzled receptors and LRP5/6 co-receptors, leading to the stabilization and nuclear translocation of β-catenin (Qin et al. 2024). One key component of this pathway is WNT Ligands, secreted proteins which initiate the signaling cascade. WNT ligands are lipid modified and have a variety of roles in embryonic development (Basson, 2012). Frizzled receptors are cell surface receptors that bind to WNT ligands. β-Catenin acts as the central mediator that enters the nucleus to activate target gene transcription, and TCF/LEF transcription factors bind to β-catenin to regulate gene expression (Nusse and Clevers, 2017; Steinhart and Angers, 2018).
Notch Pathway:
The Notch pathway plays a role in cell differentiation by influencing cell fate decisions, particularly in the nervous system, blood cells, and epithelial cells (Brandstadter and Maillard. 2019). The pathway also is a key contributor in maintaining cell polarity, proliferation, apoptosis and epithelial-mesenchymal transition (Parambath et al., 2024) This pathway operates through direct cell-cell interactions and is activated when Notch receptors on one cell bind to Delta or Jagged ligands on an adjacent cell. This binding triggers the cleavage of the Notch receptor and releases the Notch Intracellular Domain (Basson, 2012). The NICD then translocates to the nucleus, where it associates with the transcriptional regulator RBP-Jκ to activate target genes. Key components of this pathway include the transmembrane Notch receptors (Notch1-4) and their ligands, Delta and Jagged, which are essential for the pathway's activation and function (Miyamoto and Weinmaster. 2009)
Hedgehog Pathway:
The Hedgehog pathway is essential for the differentiation and development of various tissues, including the neural tube, limbs, and skin, as well as helping to maintain stem cells in adults. Activation of this pathway begins when Hedgehog ligands bind to the Patched (PTCH) receptor. This binding alleviates PTCH's inhibition of the Smoothened (SMO) receptor, thereby activating downstream signaling (Carballo et al. 2018). A key component of the Hedgehog pathway includes the Hedgehog ligands (Sonic, Indian and Desert), which are secreted proteins that initiate the pathway (Basson, 2012). The PTCH receptor inhibits the pathway in the absence of these ligands, while the SMO receptor activates the pathway once Hedgehog binds to PTCH. GLI transcription factors then regulate target gene expression in response to the activation of the pathway (Briscoe and Therond, 2013).
TGF-β/SMAD pathway:
The TGF-β/SMAD pathway is important for the differentiation of various cell types, including mesenchymal, epithelial, and immune cells. It also plays significant roles in cell proliferation, apoptosis, and extracellular matrix production (Flanders et al., 2009). Activation of this pathway occurs when TGF-β ligands bind to type II and type I serine/threonine kinase receptors, leading to the phosphorylation and activation of SMAD proteins. The key components of this pathway include TGF-β ligands, which are transforming growth factor-beta (TGF-β) proteins that initiate signaling, and the type I and II receptors that propagate the signal. Upon activation, receptor-regulated SMADs (SMAD2/3) are phosphorylated and form complexes with the common-mediator SMAD (SMAD4). These complexes then regulate gene expression to mediate the pathway's effects (Derynck and Zhang, 2003).
JAK-STAT Pathway:
The JAK-STAT pathway mediates responses to cytokines and growth factors, thereby influencing the differentiation of immune cells, hematopoietic cells, and other cell types. Activation of this pathway begins when cytokines bind to their receptors, leading to the activation of Janus Kinases (JAKs) (Hu et al. 2023). JAKs phosphorylate signal transducers and activators of transcription (STATs), allowing them to dimerize and translocate to the nucleus to regulate gene expression (Garrido-Trigo and Salas. 2019). Cytokine receptors are key components of the JAK-STAT pathway, which bind cytokines and activate JAKs. Other key components include JAKs, which are tyrosine kinases responsible for phosphorylating and activating STATs, and STATs which are transcription factors that mediate gene expression in response to cytokine signaling (Bezbradica and Medzhitov, 2009).
Hippo Pathway:
The Hippo pathway plays a role in controlling organ size by regulating cell proliferation, apoptosis, and stem cell self-renewal. It also influences the differentiation of various cell types. Activation of this pathway involves a kinase cascade that ultimately phosphorylates and inactivates the transcriptional co-activators YAP and TAZ. Key components of the Hippo pathway include MST1/2 (Mammalian Ste20-like Kinase), which initiates the kinase cascade, and LATS1/2 (Large Tumor Suppressor Kinase), which phosphorylate and inhibit YAP/TAZ (Zhou et al. 2024). When not phosphorylated, yes-associated protein/ transcriptional co-activator with PDZ-binding motif (YAP/TAZ) act as transcriptional co-activators that regulate gene expression. They partner with TEAD (TEA Domain Transcription Factors) to regulate target gene expression, thereby influencing cell behaviour and fate.
ERK/MAPK pathway:
The ERK/MAPK pathway is essential for regulating cell proliferation, differentiation, and survival, playing a pivotal role in the differentiation of various cell types in response to growth factors and other extracellular signals. Activation of this pathway involves a kinase cascade where MAPK/ERK is activated by MEK, which is in turn activated by RAF (Bahar et al. 2023). Key components of the ERK/MAPK pathway include RAF (Rapidly Accelerated Fibrosarcoma Kinase), which initiates the kinase cascade, and MEK (MAPK/ERK Kinase), which activates ERK through phosphorylation. ERK (Extracellular Signal-Regulated Kinase) then phosphorylates various target proteins, including transcription factors such as ELK1 and c-FOS, to regulate gene expression and influence cell behaviour (Arthur and Ley, 2013; Yue and López, 2020).
How It Is Measured or Detected
Pathway |
Method of Measurement |
Description |
Reference |
OECD Approved Assay |
WNT/β-Catenin |
Western Blot |
Detects β-catenin protein levels by using specific primary antibodies. |
Zhang et al., 2019 |
No |
Immunofluorescence |
Evaluated β-catenin expression in the nucleus and cytoplasm |
Rong et al., 2022 |
No |
|
qPCR |
Measures expression of Wnt/β-catenin signaling pathway-related genes and mRNA levels. |
Wang et al., 2023 |
No |
|
Luciferase reporter assay |
Evaluates WNT/β-catenin pathway activity by performing reporter gene assays with luciferase expression vectors containing wild-type and mutant TCF/LEF binding sites, comparing luciferase activities |
Fröhlich et al., 2023 |
No |
|
Notch |
qPCR |
Quantifies mRNA levels of Notch1,3 and 4 as well as notch signalling downstream targets. |
Ibrahim et al., 2017 |
No |
Immunofluorescence |
Evaluated notch fluorescence levels using anti-Notch1 primary antibody |
Rong et al., 2022 |
No |
|
Western Blot |
Measures protein expression of Notch1 using bicinchoninc acid protein assay kit. |
Rong et al., 2022 |
No |
|
Hedgehog |
Immunohistochemistry |
Measures expression of levels of SHH pathway members. |
Ke et al., 2020 |
No |
Western Blot |
Detects GLI protein levels and their activation state. |
Ke et al., 2020 |
No |
|
TGF-β/SMAD |
ELISA |
Quantifies TGF-β ligand concentration in samples. |
Rouce et al., 2016 |
No |
Immunofluorescence |
Visualizes nuclear vs. cytoplasmic localization of SMAD2/3. |
Liu et al, 2016 |
No |
|
Western Blot |
Detects phosphorylation status of SMAD2/3 proteins. |
Liu et al., 2016 |
No |
|
qRT-PCR |
Quantifies mRNA levels of AKT1 and PI3K. |
Xia and Tang 2023 |
No |
|
JAK-STAT |
Western Blot |
Measures levels of JAK2 and STAT3. |
Broughton and Burfoot, 2001; Mao et al., 2023 |
No |
Electrophoretic Mobility Shift Assay (EMSA) |
Measures DNA-binding activity of STAT proteins to specific response elements. |
Broughton and Burfoot; Jiao et al., 2003 |
No |
|
Hippo |
Western Blot |
Detects expression levels of Hippo pathway proteins. |
Wang et al., 2024; Chen et al., 2020 |
No |
Immunofluorescence |
Visualizes nuclear vs. cytoplasmic localization of Hippo pathway expression. |
Chen et al., 2020; |
No |
|
Chromatin immunoprecipitation (ChIP) |
Measures expression of genes regulated by the Hippo pathway. |
Wang et al., 2024; |
No |
|
ERK/MAPK |
Western Blot |
Detects the phosphorylation state of MAPK family members (ERK, JNK, p38), indicating activation. |
Tan et al. 2022; Xia and Tang 2023 |
No |
qRT-PCR |
Quantifies mRNA levels of JNK, MAPK1(ERK), and MAPK14(p38) |
Xia and Tang 2023 |
No |
Domain of Applicability
Taxonomic applicability: Altered signaling is applicable to all animals as cell signaling occurs in animal cells. This includes vertebrates such as humans, mice and rats (Nair et al., 2019).
Life stage applicability: Life stage applicability is pathway dependent.
Sex applicability: This key event is not sex specific.
Evidence for perturbation by a stressor: Multiple studies show that signaling pathways can be disrupted by many types of stressors including ionizing radiation and altered gravity (Su et al., 2020; Yentrapalli et al., 2013).
References
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