negative regulation of epithelial cell migration

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of epithelial cell migration. [GOC:BHF, GOC:dph, GOC:tb]

Negative regulation of epithelial cell migration is a complex process that involves a intricate interplay of signaling pathways, cytoskeletal dynamics, and cell-cell interactions. It is essential for maintaining tissue integrity, wound healing, and preventing uncontrolled cell movement that can lead to cancer metastasis. Here's a detailed breakdown of the key players and mechanisms involved:

**1. Signaling Pathways:**

* **TGF-β Pathway:** Transforming growth factor-beta (TGF-β) plays a crucial role in inhibiting epithelial cell migration. Upon binding to its receptors, TGF-β activates a signaling cascade that ultimately leads to the transcription of genes involved in cell cycle arrest, cell adhesion, and cytoskeletal reorganization. Key downstream effectors include Smad proteins, which act as transcription factors to regulate gene expression.
* **Wnt Pathway:** Wnt signaling is another important pathway that can either promote or inhibit epithelial cell migration depending on the specific context. Canonical Wnt signaling, triggered by Wnt ligands, promotes cell proliferation and survival, but also inhibits cell migration by promoting cell-cell adhesion through E-cadherin upregulation. Conversely, non-canonical Wnt signaling, primarily mediated by Wnt5a, can promote cell migration.
* **Hippo Pathway:** The Hippo pathway, also known as the Salvador-Warts-Hippo pathway, regulates organ size and cell proliferation. It can also influence cell migration. Activation of the Hippo pathway leads to the phosphorylation and inactivation of transcriptional coactivators YAP and TAZ, which suppresses the expression of genes that promote cell migration.

**2. Cytoskeletal Dynamics:**

* **Actin Filaments:** Epithelial cell migration relies on the dynamic rearrangement of actin filaments, which form the core of the cytoskeleton. Negative regulation of migration often involves the stabilization of actin filaments, preventing their depolymerization and disassembly. Proteins like RhoA and its downstream effector, Rho-associated protein kinase (ROCK), promote stress fiber formation and inhibit cell migration.
* **Microtubules:** Microtubules are another major component of the cytoskeleton. Their role in epithelial cell migration is complex and context-dependent. Some studies suggest that microtubule stabilization can suppress cell migration, while others suggest that specific microtubule modifications, like acetylation, can promote migration.

**3. Cell-Cell Adhesion:**

* **Cadherins:** Cadherins are transmembrane proteins that mediate cell-cell adhesion. E-cadherin, a key component of adherens junctions, plays a major role in epithelial cell adhesion and the maintenance of tissue integrity. Increased E-cadherin expression and the formation of strong adherens junctions can inhibit cell migration.
* **Integrins:** Integrins are transmembrane receptors that connect the extracellular matrix (ECM) to the intracellular cytoskeleton. They play a crucial role in cell adhesion, migration, and survival. Integrin signaling can be modulated to regulate epithelial cell migration. For instance, specific integrins can promote adhesion and inhibit migration, while others can facilitate migration by mediating cell-ECM interactions.

**4. Extracellular Matrix (ECM):**

* **ECM Remodeling:** The ECM is a complex network of proteins and carbohydrates that provides structural support and influences cell behavior. The ECM can be remodeled through the degradation of its components by enzymes like matrix metalloproteinases (MMPs). Increased MMP activity can promote epithelial cell migration by degrading the ECM and creating pathways for cells to move. Conversely, the inhibition of MMPs can suppress cell migration.

**5. Other Factors:**

* **Cell Cycle Regulation:** Epithelial cell migration is often tightly coupled to the cell cycle. The transition from G1 to S phase, which marks the initiation of DNA replication, can promote cell migration. Conversely, cell cycle arrest in G1 or G2 phases can inhibit migration.
* **Microenvironment:** The surrounding microenvironment, including factors like oxygen levels, nutrients, and the presence of other cell types, can influence the regulation of epithelial cell migration. For example, hypoxia, or low oxygen levels, can stimulate cell migration in certain contexts.

In summary, the negative regulation of epithelial cell migration is a multifaceted process involving the interplay of signaling pathways, cytoskeletal dynamics, cell-cell adhesion, ECM remodeling, and other factors. Understanding these mechanisms is crucial for developing therapeutic strategies for diseases that involve abnormal cell migration, such as cancer metastasis and wound healing complications.'
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Proteins (3)

Compounds (3)