- Email: [email protected]
Cell structure and dynamics
15
Cell structure and dynamics Editorial overview Daniel Louvard and Trina Schroer Current Opinion in Cell Biology 2002, 14:15–17 0955-0674/02/$ — see front matter © 2002 Elsevier Science Ltd. All rights reserved.
Daniel Louvard Laboratory `Morphogenesis and Cellular Signalisation’, 26, rue d’Ulm – 75231, Paris CEDEX 05, France; e-mail: [email protected]
Daniel Louvard currently holds positions as director of the research division of the Institut Curie and also director of the graduate course on molecular cell biology at the Institut Pasteur. He has continued to direct his own research group, which is primarily interested in the molecular mechanisms controlling and regulating cellular functions such as cell motility, cell shape and cellular signalling with a particular emphasis on polarized epithelial cells. Trina Schroer Department of Biology, 220A Mudd Hall, The Johns Hopkins University, Baltimore, MD 21218, USA; e-mail: [email protected]
Trina Schroer is a Professor of Biology at Johns Hopkins University. Work in her lab is focused on the dynamics and motility of endomembranes, and how the microtubule based motor, cytoplasmic dynein, and its activator dynactin, contribute to organelle dynamics and cytoarchitecture.
Originally conceived as a structural framework used by cells to provide cytoplasmic bulk, tensile strength and roadways for subcellular movements, the cytoskeleton is now known to be a highly dynamic array, which interacts with and coordinates a wide range of physiological functions. Work in the area of cytoskeletal biology continues to produce new insights at a dizzying rate. It is no longer possible to consider cytoskeletal polymers and their associated proteins as structures that function independently of the greater cellular milieu. This conceptual shift has resulted in a blurring of distinctions between classical cell biological disciplines and has led students of the cytoskeleton to explore new questions. In keeping with the current state of the field, the editors of Current Opinion in Cell Biology have assigned a new name to this issue; ‘Cell structure and dynamics’. The topics selected reflect the broad range of subjects that currently occupy the interest of many cytoskeletal biologists. As always, it was not possible to provide comprehensive coverage of all new developments, but rather areas were chosen to highlight particularly significant new discoveries which have emerged over the past several months. On a superficial level, this issue is organized according to classical distinctions in the cytoskeletal field: microtubules, motors, actin and actin-binding proteins, and intermediate filaments. However, many of the articles found here cross the boundaries between subfields and most, if not all, report on recent progress that extends far beyond these traditional distinctions. The first series of articles discuss mechanisms by which the microtubule cytoskeleton is assembled, disassembled and organized. The dynamic behavior of microtubule ends, in particular the protein factors that play key roles in regulating microtubule disassembly, are discussed by Cassimeris (pp 18–24). She describes recent work on the Op18/stathmin proteins, a large protein family whose in vivo functions remain enigmatic. The exact mechanism by which stathmins affect tubulin assembly is a subject of some controversy, but the recent elucidation of stathmin’s structure, detailed tubulin-binding properties and mechanisms for post-translational modification are sure to promote a clearer view. The other reviews in this first section are focused on the centrosome, the organelle that is believed to coordinate the processes of microtubule nucleation and organization. Bornens (pp 25–34) provides an up-to-date view of centrosome structure and highlights proteins that may be critical for binding microtubule minus ends at centrosomal or noncentrosomal sites. It appears that the centrosome is not simply a warehouse for tubulin nucleating and anchoring activities. In addition, the centrosome receives inputs from and stores a huge range of cellular signalling molecules. Lange (pp 35–43) provides a strong case for the centrosome being a central depot for both signaling molecules and cell cycle regulators. The critical role played by the centrosome in normal cell cycle progression is also discussed. The association of important signaling molecules with the mitotic spindle poles that derive from centrosomes may provide the cell with a mechanism to ensure that
16
Cell structure and dynamics
physiological regulators are properly apportioned between daughter cells. Microtubule plus ends are not associated with centrosomes, but instead extend into the cell periphery where they have the opportunity to interact with molecules of the cell cortex. Cytoplasmic dynein, a minus end directed microtubule motor, is thought to play an important role in this process. Dujardin and Vallee (pp 44–49) discuss recently discovered evidence in support of dynein’s role in microtubule docking at the cell surface and provide some hints as to surface and regulatory molecules that may be involved. No compendium of recent developments in the areas of cell structure and dynamics would be complete without a discussion of the molecular motors that drive subcellular movements. As our second topic, we highlight new developments in the areas of motor mechanics and cargo selection. Our understanding of the mechanochemical cycles of kinesins and myosins has matured greatly in the past few years thanks to the development of single-molecule techniques for the analysis of motor biophysics and enzymology. The insights gained using these methods, viewed in light of the known atomic structures, have provided a clear picture of how motors work. Higuchi and Endow (pp 50–57) summarize the current state of the field and describe how a limited set of motor protein structures can yield a family of proteins that differ widely with respect to directionality and processivity. The list of cargoes carried by the kinesin and dynein families of microtubule-based motors is long and ever growing. Given the diversity of molecules and structures involved, it may come as no surprise to learn that these same motors coordinate the transport of cytoskeletal proteins within axons themselves. The discovery that slow axonal transport is actually intermittent fast transport is discussed by Shah and Cleveland (pp 58–62). For slow transport, and indeed most cargoes, the molecular mechanism for motor binding remains poorly understood. However, as discussed by Kamal and Goldstein (pp 63–68), it is becoming clear that transmembrane proteins and other components of the classical membrane cytoskeleton can serve as microtubule-based motor receptors. In keeping with this theme, Hammer and Wu (pp 69–75) review recent work revealing that the actin-based motor myosin V may interact with membranes via the small GTPase, Rab27. The third set of topics covered here concentrates on the dynamics, regulation and interactions of the actin cytoskeleton. The predominant theme of this section is the way in which actin filaments are recruited to and/or assembled at specific subcellular locations to allow the cell to undergo shape changes in response to extracellular signals. An example of this is seen in the process of endocytosis, when cells invaginate and ultimately engulf bits of membrane that then move centripetally to fuse with similar membranes. As reviewed by Schafer (pp 76–81),
the actin cytoskeleton appears to play multiple roles in the early endocytic pathway. Several recent studies have defined a number of important actin-dependent events and identified some of the molecules that drive them. As expected, a key player is the Arp2/3 complex, a fascinating molecular assembly whose structure was recently solved at low and high resolution [1,2]. Many proteins that participate in endocytosis are thought to stimulate actin assembly by activating Arp2/3 directly, whereas others act indirectly by binding members of the WASP (Wiskott–Aldrich syndrome protein) family of Arp2/3 activators. The mechanism of activation of WASP itself, and its regulation, is reviewed by Caron (pp 82–87). WASP proteins are part of a much larger protein superfamily whose members have been implicated in the regulation of actin filament dynamics and organization in an enormous array of cell and tissue types. As discussed by Renfranz and Beckerle (pp 88–103), these proteins share a number of features including the ability to bind poly-proline rich ligands. All members of this important family of regulatory proteins contain multiple interaction domains, which suggests that they serve to integrate a variety of physiological inputs, including those mediated by small GTP-binding proteins of the rho superfamily. Although actin filaments in the cell cortex have the capacity to be highly dynamic, they can also be organized by actinbinding proteins into a variety of complicated and elegant arrays. An important class of actin interacting proteins is the ERM (ezrin/radixin/moesin) proteins, which serve to bind actin filaments to the plasma membrane. These fascinating molecules have the capacity to fold back on themselves to bury both their actin and membrane-binding domains. This autoinhibitory process is well understood at the structural level, but the mechanisms by which ERM protein activity is regulated are still being worked out. In their review (pp 104–109), Gautreau, Louvard and Arpin discuss mechanisms of ERM regulation and how perturbation of the normal regulatory mechanisms may lead to tumor formation. We close the volume with a discussion of the assembly and function of an important and abundant family of intermediate filaments, the keratins. Omary and Coulombe (pp 110–122) provide a comprehensive review of the structural features that define and distinguish keratins in tissues as diverse as horn and epithelial cells. Long thought to function only as structural stabilizers of epithelial cells and their derivatives, keratins are now known to participate in a range of cellular functions. Thus, like the microtubule and actin cytoskeletons, intermediate filaments have emerged as important players that serve to integrate signaling molecules and regulatory activities. The cytoskeleton and its diverse array of binding proteins defines cell structure and function, making it of central importance to our understanding of the cell as a whole. Future work is sure to uncover even more molecules that
Editorial overview Louvard and Schroer
govern filament assembly and disassembly. Still to come is a detailed understanding of how filament dynamics are controlled in time and space, and how the microtubule, intermediate and actin filaments systems interact with each other to yield the complicated structures and cellular behaviors seen in higher organisms.
17
References 1.
Volkmann N, Amann KJ, Stoilova-McPhie S, Egile C, Winter DC, Hazelwood L, Heuser JE, Li R, Pollard TD, Hanein D: Structure of Arp2/3 complex in its activated state and in actin filament branch junctions. Science 2001, 293: 2456-2459.
2.
Robinson RC, Turbedsky K, Kaiser DA, Marchand J-B, Higgs HN, Choe S, Pollard TD: Crystal structure of Arp2/3 complex. Science 2001, 294:1679-1684.
Cell structure and dynamics Editorial overview Daniel Louvard and Trina Schroer Current Opinion in Cell Biology 2002, 14:15–17 0955-0674/02/$ — see front matter © 2002 Elsevier Science Ltd. All rights reserved.
Daniel Louvard Laboratory `Morphogenesis and Cellular Signalisation’, 26, rue d’Ulm – 75231, Paris CEDEX 05, France; e-mail: [email protected]
Daniel Louvard currently holds positions as director of the research division of the Institut Curie and also director of the graduate course on molecular cell biology at the Institut Pasteur. He has continued to direct his own research group, which is primarily interested in the molecular mechanisms controlling and regulating cellular functions such as cell motility, cell shape and cellular signalling with a particular emphasis on polarized epithelial cells. Trina Schroer Department of Biology, 220A Mudd Hall, The Johns Hopkins University, Baltimore, MD 21218, USA; e-mail: [email protected]
Trina Schroer is a Professor of Biology at Johns Hopkins University. Work in her lab is focused on the dynamics and motility of endomembranes, and how the microtubule based motor, cytoplasmic dynein, and its activator dynactin, contribute to organelle dynamics and cytoarchitecture.
Originally conceived as a structural framework used by cells to provide cytoplasmic bulk, tensile strength and roadways for subcellular movements, the cytoskeleton is now known to be a highly dynamic array, which interacts with and coordinates a wide range of physiological functions. Work in the area of cytoskeletal biology continues to produce new insights at a dizzying rate. It is no longer possible to consider cytoskeletal polymers and their associated proteins as structures that function independently of the greater cellular milieu. This conceptual shift has resulted in a blurring of distinctions between classical cell biological disciplines and has led students of the cytoskeleton to explore new questions. In keeping with the current state of the field, the editors of Current Opinion in Cell Biology have assigned a new name to this issue; ‘Cell structure and dynamics’. The topics selected reflect the broad range of subjects that currently occupy the interest of many cytoskeletal biologists. As always, it was not possible to provide comprehensive coverage of all new developments, but rather areas were chosen to highlight particularly significant new discoveries which have emerged over the past several months. On a superficial level, this issue is organized according to classical distinctions in the cytoskeletal field: microtubules, motors, actin and actin-binding proteins, and intermediate filaments. However, many of the articles found here cross the boundaries between subfields and most, if not all, report on recent progress that extends far beyond these traditional distinctions. The first series of articles discuss mechanisms by which the microtubule cytoskeleton is assembled, disassembled and organized. The dynamic behavior of microtubule ends, in particular the protein factors that play key roles in regulating microtubule disassembly, are discussed by Cassimeris (pp 18–24). She describes recent work on the Op18/stathmin proteins, a large protein family whose in vivo functions remain enigmatic. The exact mechanism by which stathmins affect tubulin assembly is a subject of some controversy, but the recent elucidation of stathmin’s structure, detailed tubulin-binding properties and mechanisms for post-translational modification are sure to promote a clearer view. The other reviews in this first section are focused on the centrosome, the organelle that is believed to coordinate the processes of microtubule nucleation and organization. Bornens (pp 25–34) provides an up-to-date view of centrosome structure and highlights proteins that may be critical for binding microtubule minus ends at centrosomal or noncentrosomal sites. It appears that the centrosome is not simply a warehouse for tubulin nucleating and anchoring activities. In addition, the centrosome receives inputs from and stores a huge range of cellular signalling molecules. Lange (pp 35–43) provides a strong case for the centrosome being a central depot for both signaling molecules and cell cycle regulators. The critical role played by the centrosome in normal cell cycle progression is also discussed. The association of important signaling molecules with the mitotic spindle poles that derive from centrosomes may provide the cell with a mechanism to ensure that
16
Cell structure and dynamics
physiological regulators are properly apportioned between daughter cells. Microtubule plus ends are not associated with centrosomes, but instead extend into the cell periphery where they have the opportunity to interact with molecules of the cell cortex. Cytoplasmic dynein, a minus end directed microtubule motor, is thought to play an important role in this process. Dujardin and Vallee (pp 44–49) discuss recently discovered evidence in support of dynein’s role in microtubule docking at the cell surface and provide some hints as to surface and regulatory molecules that may be involved. No compendium of recent developments in the areas of cell structure and dynamics would be complete without a discussion of the molecular motors that drive subcellular movements. As our second topic, we highlight new developments in the areas of motor mechanics and cargo selection. Our understanding of the mechanochemical cycles of kinesins and myosins has matured greatly in the past few years thanks to the development of single-molecule techniques for the analysis of motor biophysics and enzymology. The insights gained using these methods, viewed in light of the known atomic structures, have provided a clear picture of how motors work. Higuchi and Endow (pp 50–57) summarize the current state of the field and describe how a limited set of motor protein structures can yield a family of proteins that differ widely with respect to directionality and processivity. The list of cargoes carried by the kinesin and dynein families of microtubule-based motors is long and ever growing. Given the diversity of molecules and structures involved, it may come as no surprise to learn that these same motors coordinate the transport of cytoskeletal proteins within axons themselves. The discovery that slow axonal transport is actually intermittent fast transport is discussed by Shah and Cleveland (pp 58–62). For slow transport, and indeed most cargoes, the molecular mechanism for motor binding remains poorly understood. However, as discussed by Kamal and Goldstein (pp 63–68), it is becoming clear that transmembrane proteins and other components of the classical membrane cytoskeleton can serve as microtubule-based motor receptors. In keeping with this theme, Hammer and Wu (pp 69–75) review recent work revealing that the actin-based motor myosin V may interact with membranes via the small GTPase, Rab27. The third set of topics covered here concentrates on the dynamics, regulation and interactions of the actin cytoskeleton. The predominant theme of this section is the way in which actin filaments are recruited to and/or assembled at specific subcellular locations to allow the cell to undergo shape changes in response to extracellular signals. An example of this is seen in the process of endocytosis, when cells invaginate and ultimately engulf bits of membrane that then move centripetally to fuse with similar membranes. As reviewed by Schafer (pp 76–81),
the actin cytoskeleton appears to play multiple roles in the early endocytic pathway. Several recent studies have defined a number of important actin-dependent events and identified some of the molecules that drive them. As expected, a key player is the Arp2/3 complex, a fascinating molecular assembly whose structure was recently solved at low and high resolution [1,2]. Many proteins that participate in endocytosis are thought to stimulate actin assembly by activating Arp2/3 directly, whereas others act indirectly by binding members of the WASP (Wiskott–Aldrich syndrome protein) family of Arp2/3 activators. The mechanism of activation of WASP itself, and its regulation, is reviewed by Caron (pp 82–87). WASP proteins are part of a much larger protein superfamily whose members have been implicated in the regulation of actin filament dynamics and organization in an enormous array of cell and tissue types. As discussed by Renfranz and Beckerle (pp 88–103), these proteins share a number of features including the ability to bind poly-proline rich ligands. All members of this important family of regulatory proteins contain multiple interaction domains, which suggests that they serve to integrate a variety of physiological inputs, including those mediated by small GTP-binding proteins of the rho superfamily. Although actin filaments in the cell cortex have the capacity to be highly dynamic, they can also be organized by actinbinding proteins into a variety of complicated and elegant arrays. An important class of actin interacting proteins is the ERM (ezrin/radixin/moesin) proteins, which serve to bind actin filaments to the plasma membrane. These fascinating molecules have the capacity to fold back on themselves to bury both their actin and membrane-binding domains. This autoinhibitory process is well understood at the structural level, but the mechanisms by which ERM protein activity is regulated are still being worked out. In their review (pp 104–109), Gautreau, Louvard and Arpin discuss mechanisms of ERM regulation and how perturbation of the normal regulatory mechanisms may lead to tumor formation. We close the volume with a discussion of the assembly and function of an important and abundant family of intermediate filaments, the keratins. Omary and Coulombe (pp 110–122) provide a comprehensive review of the structural features that define and distinguish keratins in tissues as diverse as horn and epithelial cells. Long thought to function only as structural stabilizers of epithelial cells and their derivatives, keratins are now known to participate in a range of cellular functions. Thus, like the microtubule and actin cytoskeletons, intermediate filaments have emerged as important players that serve to integrate signaling molecules and regulatory activities. The cytoskeleton and its diverse array of binding proteins defines cell structure and function, making it of central importance to our understanding of the cell as a whole. Future work is sure to uncover even more molecules that
Editorial overview Louvard and Schroer
govern filament assembly and disassembly. Still to come is a detailed understanding of how filament dynamics are controlled in time and space, and how the microtubule, intermediate and actin filaments systems interact with each other to yield the complicated structures and cellular behaviors seen in higher organisms.
17
References 1.
Volkmann N, Amann KJ, Stoilova-McPhie S, Egile C, Winter DC, Hazelwood L, Heuser JE, Li R, Pollard TD, Hanein D: Structure of Arp2/3 complex in its activated state and in actin filament branch junctions. Science 2001, 293: 2456-2459.
2.
Robinson RC, Turbedsky K, Kaiser DA, Marchand J-B, Higgs HN, Choe S, Pollard TD: Crystal structure of Arp2/3 complex. Science 2001, 294:1679-1684.