We report here that living cells and nuclei are hard-wired such that a mechanical tug on cell surface receptors can immediately change the organization of molecular assemblies in the cytoplasm and nucleus. When integrins were pulled by micromanipulating bound microbeads or micropipettes, cytoskeletal filaments reoriented, nuclei distorted, and nucleoli redistributed along the axis of the applied tension field. These effects were specific for integrins, independent of cortical membrane distortion, and were mediated by direct linkages between the cytoskeleton and nucleus. Actin microfilaments mediated force transfer to the nucleus at low strain; however, tearing of the actin gel resulted with greater distortion. In contrast, intermediate filaments effectively mediated force transfer to the nucleus under both conditions. These filament systems also acted as molecular guy wires to mechanically stiffen the nucleus and anchor it in place, whereas microtubules acted to hold open the intermediate filament lattice and to stabilize the nucleus against lateral compression. Molecular connections between integrins, cytoskeletal filaments, and nuclear scaffolds may therefore provide a discrete path for mechanical signal transfer through cells as well as a mechanism for producing integrated changes in cell and nuclear structure in response to changes in extracellular matrix adhesivity or mechanics.Cells generate mechanical tension in their actin cytoskeleton (CSK) and exert tractional forces on their adhesions to extracellular matrix (ECM) (1). Changes in the balance of forces between cells and ECM, induced by altering matrix flexibility or adhesivity, can change cell shape and switch cells between growth and differentiation (1-5). The precise mechanism by which cell shape changes influence gene expression and cell cycle progression remains unclear. However, these regulatory effects appear to be mediated, at least in part, by associated changes in CSK and nuclear structure (1, 6-10). Thus, it is critical to understand how mechanical stresses applied to the surface membrane can promote coordinated alterations in cell, CSK, and nuclear form. Understanding this mechanism also could provide insight into mechanotransduction, the process by which cells sense and respond to external mechanical stimuli.One explanation for integrated cell shape control is that transmembrane ECM receptors, CSK filaments, and nuclear scaffolds are ''hard-wired'' together such that a mechanical pull on the surface membrane results in coordinated realignment of structural elements throughout this interconnected molecular network (11,12). This model is in direct contrast to many current models of cell mechanics, which envision the viscous fluid-like cytoplasm and surrounding elastic membrane to be the major load-bearing elements in living cells (13)(14)(15). On the other hand, microscopic studies demonstrate structural continuity between ECM molecules, transmembrane proteins, CSK filaments, and nuclear scaffolds in detergent-extracted cells (16)(17)...