Topic: Structural and signaling roles of keratin cytoskeletal assemblies; Epithelial differentiation and homeostasis in health and disease.

Our laboratory studies the biology of complex epithelia, in health and in disease, from the perspective of large family of conserved genes encoding keratin cytoskeletal proteins. These proteins polymerize to form 10-nm wide “intermediate” filaments which, in vivo, are organized in intricate cytoplasmic networks anchored at 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 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 such diseases.

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.

Lee CH, Coulombe PA (2009). Self-organization of keratin intermediate filaments into cross-linked networks. J Cell Biol. 186(3):409-21.

Coulombe PA, Kerns ML, Fuchs E (2009). Epidermolysis bullosa simplex: a paradigm for disorders of tissue fragility. J Clin. Invest. 119(7):1784-93.

Gu LH, Coulombe PA (2008). Hedgehog signaling, keratin 6 induction, and sebaceous gland morphogenesis: implications for pachyonychia congenita and related conditions. Am J Pathol. 173: 752-61.

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.

Kim S, Wong P, Coulombe PA (2006). A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature 441: 362-5. Tong X, Coulombe PA (2006). Keratin 17 modulates hair follicle cycling in a TNFa-dependent fashion. Genes & Dev. 20: 1353-64.