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Intracellular Transport Using Microtubule-Based Motors Annual Reviews www.annualreviews.org/aronline Ann. Rev. Cell Biol. 1987. 3 ." 347-78 Copyright © 1987 by Annual Reviews Inc. All rights reserved INTRACELLULAR TRANSPORT USING MICROTUBULE-BASED MOTORS Ronald D. Vale Cell Biology Program, Departmentof Pharmacology, University of California, San Francisco, California 94143 CONTENTS INTRODUCTION.............................................................................................................. 347 IN VITROSYSTEMS FOR STUDYING MICROTUBULE-BASED ORGANELLE TRANSPORT .............. 349 AxonalTransport ..................................................................................................... 349 OrgandieTransport in NonneuronalCells ................................................................ 353 CANDIDATESFORORGANELLE TRANSPORT MOTORS ......................................................... 355 Kinesin..................................................................................................................... 355 CytoplasmicDynein and OtherPossible Motors....................................................... 360 BIOCHEMICALAND STRUCTURAL CHARACTERISTICS OF ORGANELLE TRANSPORT ............... 361 Association of Motility Proteins with Organelles...................................................... 361 Direction ~f Movementon the MicrotubuleLattice ................................................... 363 APERSPECTIVE INVIVO .................................................................................................. 364 Role of Microtubule Polarity and Motility Proteins in Organelle Sorting within the Cell............................................................................................................... 364 Role of Microtubule-Based Motors in Secretion, Endocytosis, and the Spatial Oryanizationof Oroanelles............................................................................ 368 by University of California - San Francisco on 03/16/07. For personal use only. CONCLUSION................................................................................................................. 372 Annu. Rev. Cell. Biol. 1987.3:347-378. Downloaded from arjournals.annualreviews.org INTRODUCTION Eukaryotic cells contain distinct membrane-boundcompartments that serve specialized functions. Whilesuch an organizationof the intracellular environmenthas clear advantages, it necessitates a meansof transferring material between membrane-bound compartments. This intracellular 347 0743-4634/87/1115~3347502.00 Annual Reviews www.annualreviews.org/aronline 348 VALE traffic is mediatedby specialized transport organelles that shuttle proteins and lipids between compartments (Farquhar 1985; Kelly 1985). Both membrane-bound compartments and filamentous polymers that constitute the cytoskeleton are found even in the most primitive eukary- otes. In such simple single-cell organisms, both microtubules and actin filaments are required for cell growth and multiplication (Pringle et al 1986; Novick & Botstein 1985). In addition to their structural functions, actin filaments and microtubules interact with force-generating enzymes such as myosins, dyneins, and kinesins. These motility proteins, together with elements of the cytoskeleton, play an integral role in transport between membrane-bound compartments, in the establishment of cell asymmetry,and in cell division. A great deal has been learned about the molecular mechanisms of myosin- and dynein-based movementin muscle and ciliated cells, largely because these force-generating proteins are abundant and are organized into ordered arrays in these specialized cells. Muchless is knownabout the mechanism of organelle transport and other ubiquitous forms of microtubule-based motility (Schliwa 1984), in part because the molecules involved in these processes are present in small quantities and because of the difficulties of using intact cells as experimental systems. However, within the last few years, several laboratories have succeeded in recon- stituting organelle transport in vitro, thereby providing newopportunities for investigating the mechanismof intracellular microtubule-based trans- port at a molecularlevel. Althoughthese studies are quite recent, it is.worth examining what such experiments have revealed about how microtubule- based motors function and about their involvement in organelle transport. This review covers in vitro systems for studying organelle transport and the properties of kinesin, a recently purified microtubule-based force- generating protein that is a good candidate for an organelle transport motor. This review also addresses general questions about cytoplasmic microtubule-based motors: Howdo they associate with organelles? How by University of California - San Francisco on 03/16/07. For personal use only. do their force-generating mechanismsdiffer from those of muscle myosin or ciliary dynein? Whatroles do these proteins play in intracellular sorting Annu. Rev. Cell. Biol. 1987.3:347-378. Downloaded from arjournals.annualreviews.org of organelles and the spatial organization of organelles and filaments? This review is not intended as a comprehensiveexamination of all forms of microtubule-based motility; subjects such as mitosis, for example, are only briefly mentioned. Actin-based systems for organelle transport, which are found in manylower eukaryotes and plant cells, also are not covered in this review. Comprehensivereviews are available on organelle trans- port (Schliwa 1984; Grafstein & Forman 1980; Rebhun 1972), dynein- powered ciliary movement(Gibbons 1981; Johnson 1985), and microtu- bules (Kirschner & Mitchison 1986). Annual Reviews www.annualreviews.org/aronline MICROTUBULE-BASED MOTORS 349 IN VITRO SYSTEMS FOR STUDYING MICROTUBULE-BASED ORGANELLE TRANSPORT Axonal Transport Although organelle transport occurs in virtually all eukaryotic cells, neurons are particularly well suited to the study of this phenomenonsince organelles are transported over great distances and at rapid rates (1-5/~m/ sec) within axons. Historically, componentsof axonal transport were ident- ified and defined primarily by injecting radiolabeled amino acids into neuronal ganglia and determining the rate at which proteins synthesized in the neuronal cell body are transported downthe axon to the nerve terminal (anterograde axonal transport). Such experiments showedthat subset of proteins is rapidly transported, at rates of up 400 mm/day (Lasek 1968; Grafstein & Forman 1980). It was later discovered that proteins such as nerve growth factor and toxins are transported at similar rates in the retrograde direction (from the nerve terminal toward the cell body) (Bisby 1986). The majority of proteins transported in either direction at such rapid rates are associated with organelles (Tsukita & Ishikawa 1980; Smith 1980). Fast axonal transport of organelles is distinct from transport of cytoskeletal and soluble proteins in the anterograde direction, which occurs at muchslower rates (0.2-4 mm/day)(see Lasek 1982 for discussion of slow transport). Although microtubules were implicated as essential components for fast axonal transport based upon the inhibitory effects of. microtubule- depolymerizing agents (Grafstein & Forman1980), two fundamental prob- lems hindered further progress toward elucidating the molecular basis of this transport. The first difficulty wasthat the structures involved in trans- port (30-200 nmvesicles and 25 nm microtubules) are below the resolution limit of light. These objects can be viewed in the electron microscope (Figure 1), but electron micrographs reveal nothing of the dynamics of movement. A fundamental advance was the development of video- by University of California - San Francisco on 03/16/07. For personal use only. enhanced contrast microscopy (Inoue 1981; Allen et al 1981), which Annu. Rev. Cell. Biol. 1987.3:347-378. Downloaded from arjournals.annualreviews.org allows 30-nmvesicles and microtubules to be viewed in real time and in their native state (Figure 1). Using the video microscopeto study the squid giant axon, Allen et al (1982) observed active transport of numeroussmall vesicles (30-200 nm diameter), which were not visualized in previous studies of axons by conventional light microscopy. These vesicles moved at velocities of 1-5 #m/sec, which was consistent with previously deter- minedrates of fast transport of labeled proteins. The complex organization of the intact axonal cytoplasm presented additional difficulties in the study of the mechanismof fast axonal trans- port. Electron micrographs of axoplasm showed a dense network of cyto- Annual Reviews www.annualreviews.org/aronline 350 VALE Figure I The interior of axons viewed by electron (A) and light (B) microscopy. Panel A shows a turtle optic nerve that was rapid frozen, fractured, shallow-etched, and rotary shadowed, as described by Schnapp & Reese (1982). This electron micrograph (50,000 x ) shows two organelles in a dense network of neurofilaments and cross-bridging elements. The arrow points to amicrotubule in the fracture plane. Panel B shows the squid giant axon viewed by video-enhanced differential interference contrast microscopy (10,000 x ), as previously by University of California - San Francisco on 03/16/07. For personal use only. described (Allen et a1 1982; Vale el a1 1985a). Neurofilaments are not visible by this technique, Annu. Rev. Cell. Biol. 1987.3:347-378. Downloaded from arjournals.annualreviews.org but individual microtubules can be discerned; one can be seen between the two arrows. Transport
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