Crossroads on Cytoskeletal Highways

connector proteins have been discovered that associate Elaine Fuchs* and Yanmin Yang with multiple cytoskeletal networks, integrating old Howard Hughes Medical Institute functions and creating new ones. As the roles of these Department of Molecular Genetics connectors unravel, it has become increasingly clear and Cell Biology that they are tailored to suit the tissue-specific needs The University of Chicago for cytoskeletal dynamics in cells. The functions of these Chicago, Illinois 60637 connectors are as intriguing and complex as the networks themselves. IFs and Their Associated Plakin Proteins: Mechanical As prokaryotes shed their tough, resilient cell walls and Integrators of Cellular Space Tailored for Different evolved into eukaryotes, intricate and dynamic infraCellular Designs of Higher Eukaryotes structures emerged to enable cells to survive against The cytoarchitecture of higher eukaryotic cells varies the physical and chemical assaults of the environment, tremendously, ranging from long and slender neurons and to allow organisms to develop elaborate cell shapes to resilient, stratified epidermal cells able to survive at and multicellular dependency. Cytoplasmic microtuthe body surface without hair, feathers, or an exoskelebules (MTs) evolved for intracellular trafficking of vesiton to protect them. IF networks and their associated cles, organelles, and proteins, and actin microfilaments proteins contribute heavily to this heterogeneity. While (MFs) were utilized for cell polarity, contractile, and mithe ability of IFs to act as mechanical reinforcers seems gratory processes. A third cytoskeletal network, interto be their universal property, IFs meet specialized cymediate filaments (IFs), evolved later as exoskeletal toskeletal requirements through their divergent searmors gave way to endoskeletons and higher eukaryquences and expression patterns, which in turn lead to otes acquired the need for mechanical integrators of versatility in their physical properties and relative abunthe cytoplasm. Thus, although many lower eukaryotes dance, and in the proteins that associate with them. survive perfectly well without cytoplasmic IFs, humans As IFs evolved to provide infrastructures, it became lacking IFs can become the unhappy bearers of degenequally advantageous to utilize IFs in specialized ways erative disorders. IFs are especially abundant in verteby integrating them with other cellular components. In brate tissues such as epidermis and muscle that unstratified epithelia, for instance, IFs attach to desmodergo substantial physical stress, reflective of their somes and participate in cell–cell adhesion, and to ability to impart intracellular mechanical strength. hemidesmosomes, specialized integrin-mediated sites of While cell biologists were elucidating the roles of cycell–substratum adhesion. These attachments are mediated by plakins, a family of enormous (.200 kDa) coiledtoskeletal networks and the intricacies of proteins assocoil dimeric proteins, related by sequence and by their ciated with each network, they began to observe that ability to act as molecular bridges between cytoskeleton agents perturbing one network often affected the others, and other cellular structures (Table 1). The prototypes of and that functions ascribed to one network were somethis family are desmoplakin, bullous pemphigoid antigen times also features of another. In the past few years, 1e (BPAG1e), and plectin, all able to associate with IFs through their carboxy tail segments. Plakins complete * To whom correspondence should be addressed (e-mail: lain@ midway.uchicago.edu). their links between IFs and adhesive junctions through