Keratin intermediate filaments: intermediaries of epithelial cell migration

Abstract

Migration of epithelial cells is fundamental to multiple developmental processes, epithelial tissue morphogenesis and maintenance, wound healing and metastasis. While migrating epithelial cells utilize the basic acto-myosin based machinery as do other non-epithelial cells, they are distinguished by their copious keratin intermediate filament (KF) cytoskeleton, which comprises differentially expressed members of two large multigene families and presents highly complex patterns of post-translational modification. We will discuss how the unique mechanophysical and biochemical properties conferred by the different keratin isotypes and their modifications serve as finely tunable modulators of epithelial cell migration. We will furthermore argue that KFs together with their associated desmosomal cell–cell junctions and hemidesmosomal cell–extracellular matrix (ECM) adhesions serve as important counterbalances to the contractile acto-myosin apparatus either allowing and optimizing directed cell migration or preventing it. The differential keratin expression in leaders and followers of collectively migrating epithelial cell sheets provides a compelling example of isotype-specific keratin functions. Taken together, we conclude that the expression levels and specific combination of keratins impinge on cell migration by conferring biomechanical properties on any given epithelial cell affecting cytoplasmic viscoelasticity and adhesion to neighboring cells and the ECM.

Regulation of keratin network dynamics by the mechanical properties of the environment in migrating cells

“…Given the reported effects of keratins on cell migration 7,8 , we assessed the consequences of K5 overexpression on nHEK migration. In comparison to nHEKs transfected with a construct coding for cytoplasmic YFP, K5-YFP nHEKs migrated slower (0.66 ± 0.0026 µm.min −1 versus 0.89 ± 0.0035 µm.min −1 ; Supplementary Fig.…”

“…The latter function is supported by the separate anchorage of the actin and keratin system to focal adhesions and hemidesmosomes 29,[42][43][44] , respectively, and the localization of both systems in separate layers with only limited connectivity (this work; cf. see also 8,45,46 ). The consequence for mechanical coupling of the two biophysically very different systems is an increase in migratory persistence.…”

Keratin Dynamics and Spatial Distribution in Wild-Type and K14 R125P Mutant Cells—A Computational Model

“…These are essential to cells since they provide not only mechanical resilience [1][2][3][4], but are also involved in many cell and tissue functions such as cell growth, proliferation, wound healing, migration, etc. [5][6][7][8][9][10][11][12][13][14][15]. Altogether 54 keratin genes have been discovered so far [16].…”

Model for Bundling of Keratin Intermediate Filaments

“…In this study, we consider IFs consisting of keratin molecules that we will refer to as keratin intermediate filaments (KIFs). They are typically expressed in epithelial cells ( 4 , 12 , 13 ). Observations in live cells revealed increased deformability of keratin-deficient epithelial cells ( 14 , 15 ).…”