The Cytoskeleton as Regulator of Cell Signaling Pathways

The actin cytoskeleton, microtubules, and intermediate filaments control cell signaling. Several filament systems can cooperate to regulate the same signaling pathway. The cytoskeleton regulates the location, duration, and intensity of signaling through a diverse set of mechanisms. These mechanisms range from force generation to sequestration of signaling regulators. The PI3 kinase‒Akt and Rho‒Rock pathways are major targets for cytoskeleton-dependent control. At the same time, these signaling routes also regulate cytoskeletal properties. Different isoforms of filament building blocks are produced, often in a cell type-dependent fashion. The combination of isoforms and numerous post-translational modifications generate actin, microtubule, or intermediate filaments that are highly heterogeneous. This heterogeneity could fine-tune the signaling control elicited by the cytoskeleton. During interphase, filamentous actin, microtubules, and intermediate filaments regulate cell shape, motility, transport, and interactions with the environment. These activities rely on signaling events that control cytoskeleton properties. Recent studies uncovered mechanisms that go far beyond this one-directional flow of information. Thus, the three branches of the cytoskeleton impinge on signaling pathways to determine their activities. We propose that this regulatory role of the cytoskeleton provides sophisticated mechanisms to control the spatiotemporal output and the intensity of signaling events. Specific examples emphasize these emerging contributions of the cytoskeleton to cell physiology. In our opinion, further exploration of these pathways will uncover new concepts of cellular communication that originate from the cytoskeleton. During interphase, filamentous actin, microtubules, and intermediate filaments regulate cell shape, motility, transport, and interactions with the environment. These activities rely on signaling events that control cytoskeleton properties. Recent studies uncovered mechanisms that go far beyond this one-directional flow of information. Thus, the three branches of the cytoskeleton impinge on signaling pathways to determine their activities. We propose that this regulatory role of the cytoskeleton provides sophisticated mechanisms to control the spatiotemporal output and the intensity of signaling events. Specific examples emphasize these emerging contributions of the cytoskeleton to cell physiology. In our opinion, further exploration of these pathways will uncover new concepts of cellular communication that originate from the cytoskeleton. globular protein that assembles into polarized filaments (F-actin) with barbed and pointed ends. contractile actin–myosin complex. belt-shaped; located basal of tight junctions; anchorage site for actin filaments. acetylates α-tubulin on Lys40. button-like contact between adjacent cells; abundant in epithelia; anchors keratin filaments. minus-end directed microtubule motor. noncellular three-dimensional matrix of secreted macromolecules; serves as scaffold; communicates with cytoplasmic cytoskeleton through integrins and other receptors. extracellular signal-regulated kinases 1 and 2; serine/threonine MAP kinases; part of the signal transduction cascade Ras-Raf-MEK-ERK1/2. site of cell–matrix attachment; FA assembly involves integrins and actin filaments. nonreceptor protein tyrosine kinase; located at focal adhesions. diverse group of eukaryotic cell surface receptors, often residing in plasma membrane; respond to extracellular stimuli (light, various ligands); transmit information to the cell interior. filaments that are not polarized; six protein families. transmembrane proteins; connected to F-actin via paxillin, talin, and vinculin. IF proteins, particularly abundant in epithelial cells. microtubule motors; most are plus-end directed. mitogen-activated protein kinase; includes ERK1/2. complex of mRNA and protein; mRNPs can assemble into granules. α/β tubulin dimers polymerize into tubes; polarized, with plus- and minus-ends. conventional (class II) myosin collaborates with F-actin to produce contractile force; involved in cell migration. Unconventional (class I) myosins interact with membranes to generate, sense, or maintain tension; other unconventional myosin classes with various roles, such as movement of cargo on F-actin. phosphorylates hydroxyl group of phosphatidylinositol in position 3 of inositol ring. Class I PI3Ks primarily phosphorylate PI4,5P2; this produces PIP3. phosphatase and tensin homolog; dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate in position 3. located in plasma membrane; binding of hormone, growth factor, or cytokines to extracellular domain stimulate kinase activity of cytoplasmic domain. small GTPase family; ∼20 members, including RhoA, Rac1, Cdc42; active when GTP-bound; inactive when GDP-bound; important for actin remodeling, cell migration, cell–cell contacts, cell proliferation. stimulates GTPase activity; GTP hydrolysis deactivates Rho; >80 proteins identified. binds Rho-GDP, three proteins identified. promotes for Rho GTPases GDP release and subsequent binding of GTP; >60 proteins identified; GEF-H1 is a Rho GEF. Rho-associated, coiled-coil containing serine/threonine protein kinases; downstream effectors of RhoA; control cell shape and actomyosin contractility; Rock1 and Rock2 have overlapping and unique functions. belt-like zone in epithelial cells; barrier between apical and basolateral membrane domains; seals space between neighboring cells; restricts movement of molecules through paracellular space. secreted Wnt proteins are growth factors; bind receptors in plasma membrane, which causes stabilization and nuclear translocation of β-catenin; nuclear β-catenin associates with transcription factors to activate gene expression; Wnt signaling controls development, cell differentiation, and migration.