Mechanochemical Signaling Directs Cell-Shape Change

Abstract

For specialized cell function, as well as active cell behaviors such as division, migration, and tissue development, cells must undergo dynamic changes in shape. To complete these processes, cells integrate chemical and mechanical signals to direct force production. This mechanochemical integration allows for the rapid production and adaptation of leading-edge machinery in migrating cells, the invasion of one cell into another during cell-cell fusion, and the force-feedback loops that ensure robust cytokinesis. A quantitative understanding of cell mechanics coupled with protein dynamics has allowed us to account for furrow ingression during cytokinesis, a model cell-shape-change process. At the core of cell-shape changes is the ability of the cell's machinery to sense mechanical forces and tune the force-generating machinery as needed. Force-sensitive cytoskeletal proteins, including myosin II motors and actin cross-linkers such as a-actinin and filamin, accumulate in response to internally generated and externally imposed mechanical stresses, endowing the cell with the ability to discern and respond to mechanical cues. The physical theory behind how these proteins display mechanosensitive accumulation has allowed us to predict paralogspecific behaviors of different cross-linking proteins and identify a zone of optimal actin-binding affinity that allows for mechanical stress-induced protein accumulation. These molecular mechanisms coupled with the mechanical feedback systems ensure robust shape changes, but if they go awry, they are poised to promote disease states such as cancer cell metastasis and loss of tissue integrity.The concept ''form begets function begets form'' provides an excellent foundation for understanding the behavior of biological systems. Even specialized cells, the smallest unit of complex living systems, perform all of the necessary functions of an organism by assuming distinct shapes, mechanical properties, and physical behaviors. Different cell types use a common set of cytoskeletal elements to provide precise physical support for their distinct functions. For example, red blood cells and neurons have very different shapes that allow them to perform their specific roles. However, they both utilize alternating patterns of actin and spectrin to form cortices with appropriate viscous and elastic properties, albeit in different structural arrangements. Perturbations to this structural network cause a breakdown in the mechanical properties, or the form, of these cells, which inhibits cell function (1,2).Fascinatingly, the physical properties of cells are both determined and acted upon by the cytoskeletal apparatus. Cells are capable of modifying their own physical properties and driving changes in cell shape in response to internal and external chemical and mechanical stimuli. These modifications occur through the remodeling of the cell cortex, the network of cytoskeletal proteins directly under the plasma membrane. Much progress has been made recently in deciphering how chemical signa...

Protein Kinase A activity is regulated by actomyosin contractility during cell migration and is required for durotaxis

“…In further consideration of what might regulate PKA activity during migration, we began to consider a cellular characteristic that is dependent on integrin-mediated adhesion, intrinsic to many cells across many modes of migration, and not typically associated with cell spreading -namely, actomyosin-dependent cellular contractility (1,13,17,50,51). Intracellular contractile forces regulate diverse aspects of signaling and cytoskeletal dynamics during cell migration (4,13,(20)(21)(22) and, importantly, these forces tend to be highest within the leading edge (23)(24)(25)(26)(27), placing them in the correct subcellular location to affect PKA activity.…”

“…The distribution of contractile forces within a migrating cell generates subcellular areas with varying degrees of intracellular tension, countered by both internal cytoskeletal scaffolds and by matrix adhesions (7,19). Intracellular contractile forces regulate myriad aspects of cell migration (4,13,(20)(21)(22) and, during the migration of many cell types, traction force tends to be highest within the leading edge, often within the lamella just behind actively protruding lamellipodia (23)(24)(25)(26)(27).…”

The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation

“…In addition to cell morphology and traction force, cell migration has also been shown to be enhanced by matrix rigidity [53][54][55][56][57][58] . Thus, to examine this relationship in the context of EOC, we seeded SKOV3 cells on soft, stiff, and rigid hydrogels (3, 25, and 125 kPa, respectively) and tracked their random migration over a period of 14 h. Less than 1% of cells plated on soft (3 kPa) gels showed significant migration, defined as a maximum displacement > 50 µm ( Figure 5A & B), and the few cells that did migrate barely exceeded this threshold ( Figure 5C and Supplemental Movie S1, top panel).…”

Aligned topography mediated cell elongation reverses pathological phenotype of in vitro cultured keloid fibroblasts

“…Disruption of normal cell shape/structure and cell arrangement pattern could lead to disease initiation and development. For examples, certain pathogenetic processes, such as cancer metastasis and loss of tissue integrity, occur when robust cell shape change happened due to the abnormal intracellular regulation . As well known, sickle‐shaped erythrocytes block blood flow in the vessels and result in various complications, like the vaso‐occlusive crisis .…”

“…For examples, certain pathogenetic processes, such as cancer metastasis and loss of tissue integrity, occur when robust cell shape change happened due to the abnormal intracellular regulation. 6 As well known, sickle-shaped erythrocytes block blood flow in the vessels and result in various complications, like the vaso-occlusive crisis. 7 Alterations of cellular structures were also observed in certain diseases such as heart failure, in which concentric hypertrophy is characterized by a decreased length-to-width aspect ratio of myocytes, which contributes to contractile dysfunction.…”