Kirschner, M.

Weber, K.

English

MPG.PuRe

Cytoplasm and cell motility Overview M. Kirschner and K. Weber* Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA and *Max Planck Institute for Biophysical Chemistry, G6ttingen, Federal Republic of Germany Current Opinion in Cell Biology 1989, 1:3-4 It is always difficult to look at recent history and predict the future. In this volume, however, it is unmistakably clear that the future course of cell biology is intimately tied to understanding the structure and organization of the cell, and that much of this understanding will be won on the battlefields of cytoskeletal research. There will be several important theaters of operations and several new technologies to be employed, but the overall goals are still the same as the original ones: the understanding ofglobal features of cell behavior including cell movement, cell division, cell differentiation, and multicellular interac- tions in tissue formation. The footsoldiers in these campaigns are still the major structural cytoskeletal proteins themselves. Though regu- latory molecules and associated factors will modify their activities, many of the properties of the polymers will be determined by the intrinsic properties of the major sub- units. It is clear that, unfortunately, we still don't under- stand clearly what these activities are. In the past few years the intrinsic dynamic properties of these simple structural polymers have been investigated by using new method- ologies. The structural basis for dynamic instability and oscillations in microtubules remains an important area of study for both cell morphogenesis and mitosis. Yet, we still lack detailed structures for tubulin and its associ- ated proteins. Intermediate filaments have become more dynamic and responsive and it is becoming clear that their remodelling is under cell cycle control, and subject to phosphorylation reactions that may regulate assembly. The beginnings of an understanding of how their overall morphology is regulated may be emerging with detailed studies of the interaction of intermediate filaments with other structural proteins. For actin, the evidence for dy- namics in the cell is convincing, but the molecular basis has not yet been established. Just as the number of pro- teins that interact with actin appeared to be growing to an unmanageable level, the promise of in vivo tests of their function in genetically tractable systems like yeast and Dictyostelium has offered new hope. The accumulation of ever increasing numbers of actin- associated and microtubule-associated proteins, though representing a triumph of immunocytochemical, protein chemical and more recently recombinant DNA methods, has seemed to outsiders, as well as a few insiders, to have degenerated into mere stamp collecting. In the past few years, however, these proteins have begun to segregate themselves into distinct prototypes carrying in their se- quence casettes for different functions. The power of this approach as clearly emerged in the characterization f dystrophin, the gene product hat is defective or missing in Duchenne-Becker muscular dystrophy. This protein, identified first by mapping and sequencing, is a large pro tein with an N-terminal actin-binding domain followed by multiple triple-helical repeats first encountered in the ery- throcyte protein spectrin. A further domain displaying EF hands has unknown function. Thus, dystrophin is unmis- takably an actin binding protein; knowledge of the de- tailed structure of several actin binding proteins provided sufficient information to identify an unknown gene and to guess its function. The cytoskeletal field is now at a stage of maturity which allows the emergence of rules for structure and expression that have an impact on em- bryology and pathology. While antibodies and genetic le- sions can now quickly yield protein sequence, it is only by laboring in the vineyards of cell biological research that we can now translate these structures into putative function. Motility has always been the special province of the cy- toskeletal field and this venue has been generally for- saken by biochemists who always felt uncomfortable about moving things (in general, they preferred to re- place movement with ATPase assays). Biologists, as we all know, always liked creepy crawly things and the re- cent era has seen their triumph. Through direct visual assays, we have identified and purified both an anterior- grade motor and a retrograde motor for microtubules; the latter is a cytoplasmic form of the dynein motor of cilia and flagella. Cilia and flagella themselves are fascinat- ing as highly regulated organelles, and the recent ability to break down their structure and obtain partial motility reactions hould allow for major advances in these areas. As complicated as the cytoskeleton is,it is clearly not self- sufficient or independent. I  is primarily a responsive l- ement interpreting for example intrinsic signals for cell division and extrinsic signals for cell movement. The big questions of the mechanism of cell movement, chemo- taxis, axon elongation and morphogenesis are still largely unanswered even though they were recognized as some of the biggest questions in biology almost a century ago. We first have the problem of linkage. What carries extra- (~) Current Science Ltd ISSN 0955-0674 3 4 Cytoplasm and cell motility cellular information to the responding cytoskeleton? Re- cent studies have identified a few types of receptor sys- tems that can cross the plasma membrane with informa- tion that potentially could regulate the overall organzi- ation of the cytoskeleton. Of particular importance are the G proteins and the extracellular receptors, such as the integrins, cell adhesion molecules and the cadherins. Special adaptor molecules, perhaps like talin, must turn the extracellular information into intracellular informa- tion. Next we are faced with the problem of global orga- nization. The leukocyte must not only move but it must move in a coherent way in response to only small differ- ences in extracellular information. Here our information is still rather incomplete. Thus, an understanding of lo- cal interactions will not be enough to understand global features of cell organization. Although it is tempting to plan the next decade of cy- toskeletal research like a military campaign, such plans will undoubtedly suffer the fate of all long-range designs. Most of the difficulties stem from our failure to take a wide enough view. The modem era in cytoskeletal re- search was itself born in exciting pictures of low-reso- lution that showed for the first time that structural pro~ teins spanned the cell in intricate and purposeful designs. The conservation of these proteins was unexpected, their extreme dynamics under many circumstances was un- expected, their extreme heterogeneity was unexpected, and finally the conservation of domains of structure link- ing families of molecules uch as the intermediate fil- ament proteins and the nuclear lamins was also unex- pected. There are further forks in the trail. After real- izing that myosin was present in virtually all eukaryotic cells, it was natural to assume that it powered cell motil- ity, as it powers muscle contraction. Recent experiments, however, have shown that most cell motility can occur when the expression or translation of the myosin gene is prevented. Our view of membrane trafficking may also be too narrow; our present extensive knowledge is mostly a product of considering the membrane systems eparately from the cytoskeleton. Yet, recent methods of visualiz- ing internal membranes in whole cells have enabled us to show both intimate interaction with the cytoskeleton and a morphology that suggests that cytoskeletal interac- tions could be an important determinant in membrane function. There is no overall theme that emerges from the col- lection of essays in this issue, except hat the cytoskele- ton as a field is distinctly lacking in smugness. The un- solved processes of cell behavior still dominate the think- ing of even the most molecular of researchers. We have been rewarded by fascinating insights into protein de- sign, new principles of the regulation of protein syn- thesis, novel physico-chemical mechanisms of assembly, and glimpses into evolution and pathology. However, we still face daunting challenges of understanding overall cell organization and behavior. 

Cytoplasm and cell motility overview.

http://hdl.handle.net/11858/00-001M-0000-002C-6247-9

Cytoplasm and cell motility overview.

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