Unit 06 Pt5

Overview of Cell Movement and Motility

  • Focus on cell crawling and motility

  • Importance across various cell types

Types of Cell Movement

  • Cell Crawling

    • Classical example: Amoeba

    • Involves chemotaxis in:

      • Bacteria

      • Yeast

      • Developmental processes (e.g., neural crest cells in Drosophila)

      • Germ cell migration

      • Adult mammalian cells

        • Key immune system cells: neutrophils, macrophages, osteoclasts, fibroblasts

        • Cancer cells undergo crawling referred to as metastasis

Stages of Cell Crawling

  • Cell crawling is a regulated, complex process divided into three stages:

    1. Protrusion

      • Formation of lamellipodium (thin protrusions at the leading edge)

      • Actin-rich structures push outward for directional movement

    2. Attachment

      • Focal adhesions secure the cell to the substratum

      • Attachment involves the actin cytoskeleton interacting with the plasma membrane

    3. Traction

      • Contraction of the back end of the cell pulls cytoplasm forward

      • Facilitated by motor proteins

Characteristics of Protrusions

  • Filopodia: Long, thin, one-dimensional with bundled actin (e.g., growth cones of neurons)

  • Lamellipodia: Wider, two-dimensional sheets with a cross-linked actin mesh, found in epithelial cells and fibroblasts

  • Invadopodia (Podosomes): Larger, three-dimensional protrusions important in tissue crossing, relevant in cancer metastasis

  • Bleb: Plasma membrane detachment from the cell cortex, actin populates the extended area

Keratocytes as a Model for Lamellipodia

  • Derived from frog/fish epidermis, abundant in keratin

  • Move rapidly (30 micrometers/minute) with large lamellipodia and small trailing cell bodies

  • Experimental manipulation shows continued growth even if a portion is sliced off

Actin Dynamics in Cell Movement

  • Stationary actin network at the substrate; polymerization at the leading edge, depolymerization at the rear

  • Concept of treadmilling: plus ends grow and minus ends stabilize due to binding proteins such as cofilin

  • Actin binding proteins: ARP complexes nucleate new filament growth at the leading edge

  • Cofilin binds to ADP-actin, promoting depolymerization

  • Active filaments predominantly in T form due to delayed ATP hydrolysis

Cell Migration Mechanisms

  • Cell motion requires actin polymerization forces that interact with the substratum

  • Formation of focal adhesions mediated by integrins linking the cell to the extracellular matrix

  • Myosin motor proteins induce contraction and help propel cell movement

Regulation of Cell Polarity and Migration

  • Front to back polarity established through signaling pathways

  • Involvement of cell surface receptors and Rho family proteins:

    • Cdc42: Induces filopodia formation

    • Rac: Induces lamellipodia formation

    • Rho: Induces formation of stress fibers

  • These proteins act as molecular switches, regulating actin organization and dynamics

WAS Proteins and Pathologies

  • Wiskott-Aldrich Syndrome (WAS): Immunodeficiency associated with abnormal actin-based motility due to WASP protein mutations

    • Enhances actin nucleation via binding to ARP2/3 complexes

    • Pathological outcomes: eczema, pneumonias, infections, B cell lymphomas

Additional Types of Cell Migration

  • Chemotaxis: directed movement toward/away from chemical gradients (e.g., bacteria, neutrophils responding to infections)

  • Examples include slime mold showing directed movement toward cyclic AMP sources.