Cell Organisation and Movement

Coordination of Cell Migration

Mechanisms of Cell Migration

Leading Edge Structures

• Filopodia:

  • Thin, spike-like protrusions that extend from the leading edge of the cell.

  • Composed of tightly packed bundles of actin filaments.

  • Formed by actin regulatory proteins known as formins, which facilitate the polymerization of actin.

• Lamellipodium:

  • A broad, sheet-like extension that represents a highly dynamic region filled with a branched network of actin filaments.

  • The Arp2/3 complex plays a crucial role by enhancing the branching of actin filaments, allowing rapid extension.

• Stress Fibers:

  • These are contractile bundles of actin filaments that anchor to the substratum via focal adhesions.

  • They play an essential role in generating contractile force necessary for cell movement.

Steps of Cell Crawling

1. Extension:

   • The initial step involves the formation of the lamellipodium at the leading edge, utilizing dynamic polymerization of actin filaments to push the plasma membrane forward.

2. Adhesion:

   • The lamellipodium forms stable attachments to the extracellular matrix (ECM) through integrin proteins, which are crucial for securing the cell in position.

3. Translocation:

   • The cell body advances by flexing and contracting the cytoskeleton, effectively moving the cell forward while maintaining its adhesion to the ECM.

4. De-adhesion and Recycling:

   • Adhesions at the rear of the cell are dismantled, and components are recycled, allowing for continuous movement without losing cellular integrity.

Role of Focal Adhesions

• Components:

  • Integrins are transmembrane receptors that bind to ECM components and connect them to the actin cytoskeleton, facilitating mechanical stability.

  • They are critical for activating stress fibers that contract and pull the cell forward.

• Functionality:

  • As the cell moves, focal adhesions undergo a process where old adhesions migrate towards the back, where they are disassembled through endocytosis, ensuring cellular mobility.

Cell Mechanics and Movement

• Translocation:

  • The mechanics of cell movement involve cortical contraction, which pushes organelles such as the nucleus forward, similar to the process of squeezing toothpaste out of a tube.

• Mechanics Balance:

  • Effective cell movement is achieved through a balance of mechanical forces generated by the cytoskeleton and the opposing forces of adhesion to the ECM, ensuring stability while allowing for mobility.

Signaling Pathways in Cell Migration

• Cytokines and Growth Factors:

  • TGF-beta (Transforming Growth Factor beta):

    • A key factor that enhances healing processes and draws immune cells towards injury sites, promoting repair.

  • Platelet-Derived Growth Factor (PDGF):

    • Stimulates not only cell movement but also cell division, particularly crucial during wound healing.

• Rho Family of GTPases:

  • Activation Mechanism:

    • GTPases exist in a GDP-bound form and are activated via Guanine nucleotide exchange factors (GEFs), which promote the exchange of GDP for GTP.

    • Upon activation, they localize to the membrane and interact with downstream effectors that orchestrate changes to the actin cytoskeleton.

• Effects of GTPase Activation:

  • Rho:

    • Stimulates the formation of stress fibers, contributing to cellular contractility.

  • Rac:

    • Triggers the formation of lamellipodia, influencing directional movement.

  • Cdc42:

    • Promotes both the establishment of filopodia and the polarity of migrating cells, critical for determining the cell's direction.

Wound Healing Assay Insights

• Utilized for investigating the role of GTP-binding proteins on cell migration during the crucial process of wound closure.

  • Dominant Negative Rac:

    • Causes poor formation of lamellipodia, leading to a significant decrease in cell migration speed.

  • Dominant Negative Cdc42:

    • Results in the presence of a leading edge but misoriented migration due to failure in establishing cellular polarity.

  • Dominant Negative Rho:

    • Impairs the formation of stress fibers, subsequently lowering motility and further compromising healing processes.

Integration of Signals for Cell Motility

• The coordinated activation of Rho, Rac, and Cdc42 leads to synchronized cellular movement:

  • Cdc42 orients cells for directional movement,

  • Rac generates the leading edge that propels forward,

  • Rho organizes stress fibers and contractile machinery at the cell's rear, ensuring effective propulsion.

Pathological Aspects of Cell Migration

• Cancer Metastasis:

  • Elevated activity of Cdc42 facilitates matrix breakdown and tissue invasion, which are key features contributing to the spread of cancer cells.

  • It is notable that enhancements in Cdc42 levels and activity can induce cancer-like behaviors in otherwise normal cells, promoting aggressive characteristics.

Summary

Properly coordinated signaling pathways and dynamic cytoskeletal remodeling are fundamental for effective cell migration, especially in physiological processes such as wound healing and in pathological states such as cancer.