Lecture 6 Actin dynamics Jan 26, 2011.doc

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Cell and Systems Biology
Maurice Ringuette

Lecture 6 January 26, 2011 Cell Migration: Microfilament Dynamics The majority of the notes is verbatim from the 4 and 5 editions of Alberts and cited literature. Myosin Motors While actin polymerization can push plasma membranes to generate cellular protrusions at the leading edge, movement of cells is also dependent on the interaction of actin cytoskeleton with myosin motors. Myosin motors move along actin filament by hydrolysis of ATP to transform chemical energy into mechanical energy- hence myosin motors are often referred to as mechanochemical motors. As noted in Alberts, the myosin family is composed of several members. The focused is on myosin I and myosin II as the play key roles in promoting cellular movements. The tail of myosin I interacts with lipid bilayers, by a still poorly understood mechanism. Via its interactions with the plasma membrane and actin-filaments at the leading edge of migrating cells, its hypothesized that myosin I promotes lamellipodia and filopodia extensions. Myosin II, in a manner similar to its role in sarcomere contractions in muscle cells, promotes contraction of stress fibers and the formation of focal adhesion. Actin dynamics and force generation by myosin II motors Activation of myosin II motors by the phosphorylation of the myosin light chains leads to the formation of bipolar thick filaments which bind to actin stress fibers. Phosphorylation of the regulatory myosin light chains is mediated by MLCK (myosin light chain kinase). As a result the myosin tail is released from its folded conformation and begins assembly into a bipolar filament composed of 15-20 molecules. The myosin motor is inactivated by myosin light chain phosphatase. Contraction of actinomyosin stress fibers is likely similar to sarcomere contractions in muscle cells, except that the actin filaments have anti-parallel orientations within fibers. While not completely understood, it is presumed that myosin II heads do not interact effectively with actin filaments orientated in the opposite direction to which the motor moves. However, contractile forces are generated when the myosin heads bind to actin filaments in the right orientation and begin walking towards the + end. As a result, actin filaments of opposite orientation slide pass each other, generating forces which contribute to cellular movements. Many cells can crawl across a solid substratum Many cells move by crawling over surfaces rather than using cilia or flagella to swim. Predatory amoeba crawl continuously in search of food, and they can easily be observed to attack and devour smaller ciliates and flagellates in a drop of pond water. In animals, almost all cell locomotion occurs by crawling, with the notable exception of swimming sperm. During embryogenesis, the structure of an animal is created by the migrations of individual cells to specific target locations and by the coordinated movements of whole epithelial sheets. In vertebrates, neural crest cells are remarkable for their long-distance migrations from their sites of origin in the neural tube to a variety of sites throughout the embryo. These cells have diverse fates, becoming skin pigment cells, sensory and sympathetic neurons and glia, and various structures in the face. Long-distance crawling is fundamental to the entire nervous system: it is in this way that the actin-rich growth cones at the advancing tips of developing axons travel to their eventual synaptic targets, guided by combinations of soluble and signals bound to cell surfaces and ECM along the way. The adult animal is also seething with crawling cells. Macrophages and neutrophils crawl to sites of infection and engulf invaders as a critical part of the immune response. Osteoclasts tunnel into bone, forming channels that are filled in by osteoblasts that follow after them, in the continuous process of bone 1remodeling and renewal. Similarly, fibroblasts can migrate through connective tissues, remodeling them where necessary and helping rebuilt damaged structures at sites of injury. In an ordered procession, the cells in the epithelial lining the intestine travel up the sides of the intestinal villi, replacing absorptive cells lost at the tip of the villus. Cell crawling also has a role in many cancers, when cells in a primary tumor invade neighboring tissues and crawl into blood vessels or lymph vessels are thereby carried to other sites in the body to form metastasis. Cell crawling is a highly complex integrated process, dependent on the actin-rich cortex beneath the plasma membrane. Three distinct activities are involved: protrusion, in which actin-rich structures are pushed out at the front of the cell; attachment, in which the actin cytoskeleton connects across the plasma membrane to the substratum; and traction, in which the bulk of the trailing cytoplasm is drawn forward. In some crawling cells, such as keratocytes from the fish epidermis, these activities are closely coordinated, and the cells seem to glide forward smoothly without changing shape. In other cells, such as fibroblasts, these activities are more independent, and the locomotion is jerky and irregular. A property exhibited by all moving cells is polarity; that is, certain structures always form at the front of the cell, whereas others are found at the rear. Cell migration is initiated by the formation of a large, broad membrane protrusion at the leading edge of a cell. Video microscopy reveals that a major feature of this movement is the polymerization of actin at the membrane. In addition, actin filaments at the leading edge are rapidly cross-linked into bundles and networks in a protruding region, called a lamellipodia in vertebrate cells. In some cases, slender, fingerlike membrane projections, called filopodia, are also extended from the leading edge. These structures then form stable contacts with the underlying surface and prevent the membrane form retracting. (In some cases, filopodia act like antennae, promoting retraction). Changes in the organization of the actin cytoskel
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