Keratin filaments and soluble vimentin interact with isoform specificity to organize cell signaling.

The keratin intermediate filament (IF) cytoskeleton provides mechanical support to load-bearing epithelial cells, but its composition varies depending on cell type and tissue context. This variation, the large size of the keratin protein family, and emerging noncanonical functions of individual keratins suggest that the keratin cytoskeleton may have additional, more complicated roles. We report a surprising interaction between the keratin IF cytoskeleton in epithelial cells and soluble oligomers of vimentin, the principal IF component in mesenchymal cells. Rather than forming a cytoskeletal network, soluble vimentin functions as a recruitment factor, organizing regulatory kinases and nonmuscle myosin on keratin filaments to promote signaling. Soluble vimentin and keratin filaments interact through the intrinsically disordered head domain of each protein. Because vimentin preferentially interacts with keratin 6A-containing filaments, increasing keratin 6A expression, as occurs during skin wound healing and cancer development, triggers this myosin-activating signaling cascade. These results demonstrate how varying composition, soluble pools, and client-scaffold interactions through intrinsically disordered regions allow IFs to organize cellular signals in parallel to their canonical mechanical role, supporting context-dependent cell and tissue regulation.