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12 - roles of cytoskeleton and motor proteins in endocytic sorting

12 - roles of cytoskeleton and motor proteins in endocytic sorting

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Roles of the cytoskeleton and motor proteinsin endocytic sorting
John W. Murray*, Allan W. Wolkoff 
 Marion Bessin Liver Research Center and Department of Anatomy and Structural Biology, Albert Einstein College of Medicine,517 Ullmann Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
Received 10 July 2003; accepted 30 July 2003
Abstract
After internalization, endocytic material is actively transported through the cytoplasm, predominantly by microtubule motor  proteins. Microtubule-based endocytic transport facilitates sorting of endocytic contents, vesicle fusion and fission, delivery tolysosomes, cytosolic dispersal, as well as nuclear uptake and cytosolic egress of pathogens. Endosomes, like most organelles,move bidirectionally through the cytosol and regulate their cellular location by controlling the activity of motor proteins, and potentially by controlling microtubule and actin polymerization. Control of motor protein activity is manifest by increasedmicrotubule ‘‘run lengths’’, and the binding of motor proteins to organelles can be regulated by motor protein receptors. Amechanistic understanding of how organelles control motor protein activity to allow for endocytic sorting presents an excitingavenue for future research.
D
2003 Elsevier B.V. All rights reserved.
 Keywords:
Endocytosis; Microtubules; Actin; Rabs; Kinesin; Dynein; Myosin; Virus; Lipids
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13862. Motor proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13872.1. Kinesins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13872.2. Dyneins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13882.3. Myosins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13882.4. Conclusion from genome analysis of motor proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13883. Categorization of cytoskeletal-based motility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13883.1. Microtubule organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13893.2. Microtubule plus-end tracking. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13893.3. Actin organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13893.4. Actin rocketing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13900169-409X/$ - see front matter 
D
2003 Elsevier B.V. All rights reserved.doi:10.1016/j.addr.2003.07.008* Corresponding author. Tel.: +1-718-430-2584; fax: +1-718-430-8975.
 E-mail address:
john _ w _ murray@yahoo.com (J.W. Murray).www.elsevier.com/locate/addr Advanced Drug Delivery Reviews 55 (2003) 1385–1403
 
4. How microtubule motors localize endosomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13904.1. Endosome movement mediated by cytoplasmic dynein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13904.2. Movement of endosomes and other organelles is bidirectional . . . . . . . . . . . . . . . . . . . . . . . . . 13904.3. Endosome motility in ustilago . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13914.4. Endosome movement mediated by kinesins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13914.5. Conclusions about bidirectional movement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13915. Coordination of bidirectional movement on microtubules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13915.1. Dynein and kinesin II bind dynactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13915.2. Oppositely moving motors are not in a tug-of-war. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13916. Motor protein receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13926.1. Scaffoldsas motor protein receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13926.2. Delivery of the yeast vacuole to the bud through myo2, Vac8a and Vac17a . . . . . . . . . . . . . . . . . . . 13937. Rab proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13937.1. Rab27a-melanophilin is the receptor for myosin V and pigment granule localization . . . . . . . . . . . . . . . 13937.2. Other interactions of Rabs with motor proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13938. Trafficking of viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13948.1. Vaccinia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13948.2. Adenovirus type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13948.3. Other viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13959. Lipids and microtubule-based trafficking. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13959.1. PIP2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13959.2. Cholesterol and Niemann-Pick C disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139610. Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139610.1. Domain displacement overexpression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139710.2. Drug delivery and disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139810.3. Drugs that inhibit specific motor proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1398Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1398References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1398
1. Introduction
Recent studies have revealed an important role of microtubules and microtubule motors in endocytictrafficking. New experimental techniques and a greater knowledge base are catalyzing the scientific explo-ration of intracellular vesicular trafficking. In thisreview, we will focus particularly on how the mea-surement of microtubule and actin based movement is contributing to our understanding of endocytic processing.During receptor-mediated endocytosis, ligands bind to specific cell surface receptors and are inter-nalized within clathrin-coated pits whose constrictionleads to coated vesicle formation. Clathrin is releasedrapidly and uncoated vesicles mature into early/sort-ing endosomes[1–3].Acidification of early endo- somes[4]leads to dissociation of most receptor– ligand complexes[5,6]. Early endocytic vesiclesundergo a series of fusions and fissions resulting inthe segregation of receptor from ligand. Ligandsdestined for degradation traffic within late endo-somes to lysosomes while receptor-enriched vesiclesare recycled back to the cell surface[1,2,7,8].Microtubules are dynamic protein filaments that stretch across cells and provide a mechanical basisfor chromosome sorting, cell polarity and organellelocalization among other functions. In vivo, micro-tubules grow and shrink from the ‘‘plus-ends’’, where-as the ‘‘minus-ends’’ of the microtubules are usuallylocated at the microtubule-organizing center as well asthe apical domain in epithelial cells and the axonalterminus in neurons. The transport of endocytic con-tents from early to late endosomes is dependent onmicrotubules and microtubules can promote fusionand fission of endocytic vesicles[7,9–12]. Direct observation of endocytosis by microscopy shows that endocytic processing occurs in association with micro-tubules[8,13,14].Filamentous actin drives muscle contraction, cy-tokinesis and extension of the plasma membrane, andcan form branched, isotropic intracellular networksand well-organized bundles. It can also participate inendocytic processing events of clathrin-mediated
 J.W. Murray, A.W. Wolkoff / Advanced Drug Delivery Reviews 55 (2003) 1385–1403
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uptake and sorting from early to late endosomes[15]. Actin filaments have a ‘barbed-end’wherefilament growth tends to occur, and the barbed-endsare abundant in the cortex of the cell facing themembrane.Endocytic traffic has been shown to occur throughendocytic carrier vesicles and this hasbeen fueledthrough study of synaptic vesicles[16]. Carrievesicles have been shown to shuttle between dif-ferent organelles using an assortment of recognitionand fusion-promoting proteins (e.g. v-SNAREs, t-SNAREs). However, the physiological strategy andenergetics of these events are not easy to understand.Membrane trafficking events are complex and in-volve thousands of different kinds of proteins. Theobligatory localization of these proteins throughspace and time might be expected to create organi-zational problems: complicated machines break eas-ily. But intracellular traffic does not break easily.Instead, evolution has produced endocytic machinerythat is both complicated and robust.
2. Motor proteins
A recent analysis of the distribution of motor  proteins across eight eukaryotic species has distilledthe large array (humans have 45 kinesin, 15 dyneinand 40 myosin genes) of known motor proteins into5 kinesin, 3 dynein and 2 myosin subclasses basedon comparisonof sequences and known functionsof the motors[17].Two fifths of the myosin and kinesin genes did not fall into any subclass, andother classification schemes may provide additionalfunctional insight. However, this analysis provides auseful, simple hypothesis for understanding moto proteins. The classes can be thought of as ‘tool boxproteins as they represent the putative typesof motors that were available to ancient organisms.
2.1. Kinesins
Kinesins bind microtubules and hydrolyze ATP to producemovementtowardthefast-growing,plus-ends,of microtubules. ‘‘C-terminal’’ kinesins, which havetheir motor domains at the C-terminus of the protein,move in the opposite direction, toward the minus-ends.Of the five proposed subclasses of kinesins, conven-tional kinesin, kinesin II and Unc104 can transport cargo, while members of the C-terminal subclass mayalsoprovidethisfunction(seebelow).Mitotickinesins,as the name implies, appear to function predominantlyin mitosis.Kinesins generally exist in the iconic motor pro-tein structure of an elongated dimer with an ATP-hydrolyzing motor domain at the N-terminus fol-lowed by a central coiled coil region, where thedimers wind together, and ending in a C-terminal,light chain binding tail region. The tail region, either itself or through light chains, is frequently the site of cargo interaction. The ‘cargo’, being the vesicle, protein, RNA, or other substance that is draggedthrough the cell along microtubules. This design permits separate regulation of the ATP-hydrolysisand cargo-binding functions.Conventional kinesins (the KIF5s) have beenshown to transport mitochondria, lysosomes, endo- plasmic reticulum, mRNA and nerve axon organelles[18].Kinesin II proteins (KIF3s, KIF17) transport cargo to flagella or cilia and power intraflagellar transport,thespecific movement of vesicles throughflagella[19].Kinesin II can alsomove pigment  granules and neuronal vesicles[20].Fungi, which do not have flagella, also do not have kinesin II proteins, and a kinesin II knockout mouse has ciliarydefects and dies during embryonic development [21]. A kidney specific knockout of inesin II results in polycystic kidney disease[22].Unc104 proteins (KIF1s, KIF13s, KIF14, KIF16s) are responsible for cytosolic vesicle transport in Dictyostelium and axo-nal transport in the nematode and vertebrates[23]. Mitotic kinesins are the only subclass of motor  proteins present in every eukaryote so far sequenced.These kinesins allow chromosome segregation anddeletions are often lethal[24,25].Inhibitors of these kinesins are currently being developed as anti-tumor agents[26].C-terminal kinesins appear to be in- volved in transport of neuronal multivesicular bodiesand Golgi. Our laboratory has reported that KIFC2 is present on hepatocyte endosomes and an antibody toKIFC2 blocked minus-end movement of thesevesicles in vitro[27].Ncd, the first minus-end directed kinesin discovered, participates in mitosisand chromosome segregation in Drosophila[28].Interestingly, deletion of either KIFC2 or KIFC3 inmice produced no obvious phenotype[29,30].
 J.W. Murray, A.W. Wolkoff / Advanced Drug Delivery Reviews 55 (2003) 1385–1403
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