Cell migration relies on intricate signaling pathways that primarily orchestrate the dynamic reorganization of the actin cytoskeleton and modulate cell adhesion. Stimuli like chemokines, cytokines, and growth factors (in metazoans) and cyclic AMP (in Dictyostelium) trigger these pathways. The Rho-family GTPases act as a crucial convergence point.
Here's a breakdown of key signaling pathways involved:
The Role of Rho GTPases
Rho GTPases, including RhoA, Rac1, and Cdc42, are central regulators of the actin cytoskeleton. Each influences cell migration in distinct ways:
- RhoA: Promotes stress fiber formation and contractility through activation of ROCK (Rho-associated kinase). This is critical for retracting the rear of the cell.
- Rac1: Induces lamellipodia formation at the leading edge by polymerizing actin filaments. It also inhibits RhoA activity in specific regions.
- Cdc42: Primarily involved in filopodia formation, which are thin, finger-like protrusions that sense the environment and initiate cell polarization.
Upstream Signaling Pathways
Several upstream pathways converge on Rho GTPases to regulate their activity:
- Receptor Tyrosine Kinases (RTKs): Growth factors bind to RTKs, leading to autophosphorylation and activation of downstream signaling molecules like PI3K (phosphoinositide 3-kinase). PI3K produces PIP3, which recruits GEFs (guanine nucleotide exchange factors) that activate Rac1.
- G-protein Coupled Receptors (GPCRs): Chemokines and other chemoattractants bind to GPCRs, initiating signaling cascades that can activate RhoA, Rac1, and Cdc42 through different mechanisms involving G proteins and GEFs.
- Integrin Signaling: Integrins, which mediate cell-ECM adhesion, also trigger signaling pathways that influence Rho GTPase activity. For example, integrin engagement can activate FAK (focal adhesion kinase) and Src, which in turn regulate Rho GTPases.
- Wnt Signaling: The Wnt pathway regulates cell polarity and migration during development. In cell migration, Wnt signaling influences the activity of Rho GTPases, particularly Rac1.
Downstream Effectors
The Rho GTPases activate various downstream effectors that directly control actin dynamics and adhesion:
- Actin Polymerization and Depolymerization: WASP family proteins, activated by Cdc42, stimulate actin polymerization. Cofilin promotes actin depolymerization. These processes are crucial for lamellipodia and filopodia formation.
- Myosin II Contractility: ROCK, activated by RhoA, phosphorylates myosin light chain (MLC), enhancing myosin II activity and contractility. This generates the forces required for cell body translocation.
- Focal Adhesion Dynamics: Integrin-mediated cell adhesion to the extracellular matrix at focal adhesions also plays a crucial role. Activation of kinases like FAK (focal adhesion kinase) by integrin clustering results in phosphorylation of numerous downstream targets that regulate the dynamics of focal adhesions.
Examples
- Chemotaxis of Immune Cells: Chemokines released at sites of inflammation activate GPCRs on immune cells, triggering Rac1 activation and lamellipodia formation, guiding the cells towards the source of the chemokine.
- Cancer Cell Metastasis: Dysregulation of Rho GTPase signaling can contribute to cancer cell metastasis. For example, increased RhoA activity can promote cell invasion and migration through the extracellular matrix.
Summary
The signaling pathways involved in cell migration are complex and interconnected. They ultimately converge on the Rho GTPases, which coordinate the dynamic reorganization of the actin cytoskeleton and cell adhesion, enabling cells to move in response to various stimuli. Disrupted signaling in these pathways can contribute to diseases such as cancer and developmental disorders.
