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Conserved Microtubule–Actin Interactions in Cell Movement and Morphogenesis

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REVIEW Conserved microtubule–actin interactions in cell movement and morphogenesis Olga C. Rodriguez, Andrew W. Schaefer, Craig A. Mandato, Paul Forscher, William M. Bement and Clare M. Waterman-Storer Interactions between microtubules and actin are a basic phenomenon that underlies many fundamental processes in which dynamic cellular asymmetries need to be established and maintained. These are processes as diverse as cell motility, neuronal pathfinding, cellular wound healing, cell division and cortical flow. Microtubules and actin exhibit two mechanistic classes of interactions — regulatory and structural. These interactions comprise at least three conserved ‘mechanochemical activity modules’ that perform similar roles in these diverse cell functions. Over the past 35 years, great progress has been made towards under- crosstalk occurs in processes that require dynamic cellular asymme- standing the roles of the microtubule and actin cytoskeletal filament tries to be established or maintained to allow rapid intracellular reor- systems in mechanical cellular processes such as dynamic shape ganization or changes in shape or direction in response to stimuli. change, shape maintenance and intracellular organelle movement. Furthermore, the widespread occurrence of these interactions under- These functions are attributed to the ability of polarized cytoskeletal scores their importance for life, as they occur in diverse cell types polymers to assemble and disassemble rapidly, and to interact with including epithelia, neurons, fibroblasts, oocytes and early embryos, binding proteins and molecular motors that mediate their regulated and across species from yeast to humans. Thus, defining the mecha- movement and/or assembly into higher order structures, such as radial nisms by which actin and microtubules interact is key to understand- arrays or bundles. This allows, for example, microtubules to form a ing a basic organizing principle for dynamic morphogenesis, which, in bipolar spindle that can move chromosomes into two daughter cells turn, is a step towards understanding health-related processes such as with high fidelity, and actin to mediate muscle contraction or promote cancer, wound healing and neuronal regeneration. Recent investiga- protrusion at the leading edge of a migrating cell. tions that shed light on these elusive interactions shall be the focus of Although it is certainly true that microtubules and actin have such our review. distinct roles, it has been evident for some time that interactions between these seemingly distinct filament systems exist. Vasiliev1 ‘Structural’ versus ‘regulatory’ interactions hinted at this years ago when he showed that an intact microtubule What are the cellular and molecular bases of microtubule–actin coop- cytoskeleton was required to maintain the polarized distribution of eration? One popular viewpoint is the ‘tensegrity model2,3, in which actin-dependent protrusions at the leading edge of a migrating fibrob- actomyosin generates tension against stiff microtubule ‘struts’ and last. This suggested that the microtubule cytoskeleton somehow adhesions to the substrate to stabilize or change cell shape. Although directs proper placement of actin polymerization- and contraction- these principles may be applicable, we propose an alternative, not nec- based activities. essarily exclusive, hypothesis, in which the interactions between actin Since then, it has become clear that similar microtubule/actin inter- and microtubules may be classified as either ‘regulatory’ or ‘structural’. actions are a basic phenomenon that underlie many fundamental cel- Regulatory interactions are those in which the two systems indi- lular processes, including cell motility, growth cone guidance, cell rectly control each other through their effects on signalling cascades division, wound healing and cortical flow. In general, such cytoskeletal (Fig. 1a). The best understood example of regulatory interactions is provided by the Rho family of small GTPases, which regulate both Olga C. Rodriguez and Clare M. Waterman-Storer are in Department of Cell microtubules and actin4. For example, RhoA mediates formation of Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA contractile actin structures, such as stress fibres5, and at the same time 92037, USA. Andrew W. Schaefer and Paul Forscher are in the Department of 6 Molecular, Cellular and Developmental Biology, KBT222, Yale University, New promotes stabilization of a sub-population of microtubules .Two key Haven, CT 06520-8103, USA. Craig A. Mandato is in the Department of factors are known to function downstream of RhoA: Rho kinase, Anatomy and Cell Biology, McGill University, 3460 University Street, Montreal, which promotes contractility by increasing phosphorylation of the PQ, H3A 2B2, Canada. William M. Bement is in the Department of Zoology and regulatory light chain of myosin-2 (ref. 7), and the formin, mDia, Program in Cellular and Molecular Biology, University of Wisconsin-Madison, 8,9 1117 West Johnson Street, Madison, WI 53706, USA. which regulates actin polymerization into bundles and also medi- e-mail: [email protected]. ates microtubule stabilization10. Similarly, Rac1 activity regulates the NATURE CELL BIOLOGY VOLUME 5 | NUMBER 7 | JULY 2003 599 REVIEW Table 1 Molecular candidates for mediating structural interactions between microtubules and actin. Protein(s) Cell type/system of Localization or association Functions/roles characterization Adenomatous polyposis Drosophila syncytial Actin caps, pseudocleavage furrows , Mediates microtubule tip–actin cortex interaction to coli (APC) embryos, epithelial cells, adherens junctions and microtubule anchor and orientate mitotic spindles; promotes (refs 34–37, 44–45, 74) human colorectal cancer plus ends; binds EB1, binds β-catenin, microtubule polymerization and stabilization in cells binds the Rac GEF Asef vitro; in mice that have a mutation in the microtubule-binding domain of APC, intestinal cells fail to migrate out of the crypts CHO1 (MLKP, Mammalian cells CHO1 splice variant with actin- Bundles microtubules; required for completion of family) (ref. 92) binding domain cytokinesis Coronin (ref. 101) Budding yeast Cortical actin patches; unique among Promotes actin assembly and crosslinking coronin family for microtubule/actin binding Cytoplasmic (1) Budding yeast (1) Interacts with cortical protein (1) Microtubule capture by cortex to position dynein/dynactin (2) C. elegans Num1p mitotic spindle during cell division (refs 39, 98) (3) Mammalian fibroblasts, (2) Cortex between the AB and P1 (2) Spindle orientation astrocytes, or epithelial cells blastomeres (3) Spindle orientation; MTOC reorientation during (3) Colocalization to F-actin cortical cell motility spots and sites of cell–cell contact IQGAP1/CLIP-170 Mammalian fibroblasts and IQGAP1 binds actin; associates with IQGAP1 binds Rac and Cdc42; role in cell–cell (refs 38, 102–104) epithelial cells microtubules via CLIP-170 compaction?; Cdc42-induced cell polarity Bim1/Kar9/Myo2 Budding yeast Bim1 on microtubule plus ends is Pulls astral microtubule along actin cables into the (refs 42, 43) linked to the myosin 5 homologue bud during spindle orientation Myo2 via Kar9 MAP2c Neurons, melanoma cells Microtubule binding when Promotes microtubule growth and actin bundling (refs 61, 105) unphosphorylated; phosphorylation enables actin localization and interaction Mip-90Human fibroblasts Colocalizes with actin and Function unknown (ref. 106) microtubules Myo5a-kinesin Neurons, melanocytes Myo5a and kinesin interact in yeast May coordinate organelle transport along complex (ref. 107) two-hybrid screen microtubules and actin Myo6–D-CLIP190 Drosophila embryos Colocalize in the nervous system and Mutation phenotype suggests Myo6 mediates complex posterior pole of embryo membrane remodeling during embryogenesis and (refs 108, 109) spermatogenesis hGAR17β and COS-7, NIH 3T3, and other From overexpression and Originally identified in a search for tumour hGAR22β (Gas2- cell lines cosedimentation experiments, suppressors; some evidence for upregulation in related proteins) localizes to and binds actin and growth-arrested cells (ref. 110) microtubules (1) kakapo/short stop (1) Drosophila embryos: (1) Localizes to microtubule ends (1) Mutation phenotype suggests role in axon (2) MACF (MACF7), neurons and epidermal (2) Sites of cell–cell contact, outgrowth; wing tissue integrity vertebrate homologue muscle attachment cells colocalizes with and binds (2) Stabilizes microtubules; mediates actin– of kakapo/shortstop (2) COS-7 cells, human microtubules and actin microtubule interactions at cell periphery (ref. 18) adrenal carcinoma cells, mouse keratinocytes BPAG1a (neuronal) Mouse embryos and tissue Hemidesmosomes; both actin-binding Skin blistering phenotypes suggest a role in and BPAG1b (muscle) and microtubule-binding domains maintenance of tissue architecture; also results in (ref. 18) disorganized intermediate filaments and microtubules in degenerating neurons Plectin Vertebrate cell lines, Links intermediate filaments to actin Disease and mutation phenotypes of skin blistering (ref. 19) explants and tissues and microtubules; localizes to stress suggest a role in maintenance of tissue integrity; fibres, hemidesmosomes regulates actin organization? This list is not exhaustive, and some entries are not referred to in the text. 600 NATURE CELL BIOLOGY VOLUME 5 | NUMBER 7 | JULY 2003 REVIEW polymerization of both actin and microtubules to promote
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