The making and maintenance of complex epithelia represents an excellent paradigm to understand how groups of cells acquire relevant characteristics to form a functional tissue. Our approach to this topic consists of defining the role of keratin proteins, the main structural proteins in epithelial cells, towards the homeostasis of skin epithelia. A large group of type I and II keratin genes occur in mammalian genomes, and are regulated in a pairwise, epithelial tissue-type, and differentiation-related fashion. Keratin proteins are tasked with forming an intricate cytoplasmic network of 10-12 nm wide “intermediate” filaments anchored near the surface of the nucleus and at cell-cell and cell-matrix adhesion complexes.

A major role of keratin filaments is to endow epithelial cells and tissues with the ability to withstand mechanical stress. Mutations affecting keratin sequences, and compromising this role, underlie several inherited blistering diseases in which epithelial cells are fragile and rupture readily upon exposure to physical stress. We are studying the biochemical determinants of this important function, and pursuing novel approaches to treat keratin-based diseases. We recently showed that the natural product sulforaphane, derived from broccoli sprouts and widely known for its chemopreventive and anti-inflammatory properties, shows promise for the treatment of a specific keratin-based disease, epidermolysis bullosa simplex.

A newly defined role for keratins is to bind and modulate the activity of a variety of signaling effectors. In skin, we found that keratins impact the survival, growth, and architecture of keratinocytes, and that these contributions are physiologically important during wound repair, in the lifelong growth cycle of hair follicles, and in the context of diseases such as cancer. Ongoing efforts suggest that in addition to impacting tissue repair via an ability to stimulate protein synthesis, wound-induced keratin proteins also participate in the regulation of keratinocyte migration. Our approach to studying keratin genes, their proteins and functions in healthy and diseased epithelial tissues is broad and ranges from biochemical studies of purified proteins in vitro to gene manipulation in mouse models in vivo.

Publications:

Kerns ML, Depianto D, Dinkova-Kostova AT, Talalay P, Coulombe PA (2007). Reprogramming of keratin biosynthesis by sulforaphane restores skin integrity in epidermolysis bullosa simplex. Proc Natl Acad Sci (USA) 104: 14460-5.
PubMed Reference

Kim S. Coulombe PA (2007). Intermediate filament scaffolds fulfill mechanical, organizational, and signaling functions in the cytoplasm. Genes & Dev. 21:1581-97.
PubMed Reference

Kim S, Wong P, Coulombe PA (2006). A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature 441: 362-5.
PubMed Reference

Tong X, Coulombe PA (2006). Keratin 17 modulates hair follicle cycling in a TNFa-dependent fashion. Genes & Dev. 20: 13-53-64.
PubMed Reference

Bernot KM, Lee C-H, Coulombe PA (2005). A Small Surface Hydrophobic Patch in the Coiled-Coil Domain of Type I Keratins Mediates Tetramer Stability. J. Cell Biol. 168: 965-74.
PubMed Reference

Wong P, Coulombe PA (2003). Loss of keratin 6 (K6) proteins reveals a function for intermediate filaments during wound repair. J. Cell Biol. 163: 327-37.
PubMEd Reference

Gu LH, Coulombe PA (2007). Keratin intermediate filament function in skin epithelia: A broadening palette with surprising shades. Curr. Opin. Cell Biol. 19: 13-23.
PubMed Reference