Cytoskeletal-associated signal proteins and their downstream effectors are a common pathway for signal transduction from the extracellular matrix, soluble growth factors and physical forces, such as strain and shear stress. The effects of forces generated by increases in extracellular pressure are less well understood but may act via similar pathways. The classic pathway for initiating outside-in signaling is through the binding of cells to extracellular matrix proteins via various integrins. The mechanisms through which intracellular events alter integrin-mediated cell adhesion to matrix proteins, inside-out signaling, are less well understood. Preliminary studies in four colon cancer cell lines and primary cells from 12 human colon tumors suggest that increases in ambient pressure as low as 10mmHg stimulate colon cancer cell, cation dependant adhesiveness. This occurs synergistically with an adhesion promoting factor in serum. Based on preliminary data and what is known about physical force transduction and inside-out signaling in other cell types, the authors hypothesize that increased extracellular pressure initiates a cytoskeletally associated tyrosine kinase mediated signal transduction cascade involving focal adhesion kinase and members of the MAPK family which alters malignant colonocyte integrin binding. This proposal seeks to further define the mechanism by which pressure stimulates adhesion. The authors will identify agents that prevent pressure-stimulated tumor cell adhesion. In the study of these FAK and MAPK enzymes, the basis for a new pathway which regulates cell adhesiveness may be found.
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