A Growing Role for Keratins

Abstract

Injuries to the skin elicit homeostatic repair responses. Nearby cells increase in size and migrate to close the wound, responses that necessitate increased protein synthesis and changes in gene expression. The expression of genes encoding keratins--which form epithelial cell intermediate filaments and thus contribute to formation of a cytoskeletal scaffolding network--is up-regulated (see Omary and Ku). Noting that mouse embryos lacking keratin 17 (K17) show delays in repairing wounds to surface ectoderm, Kim et al. took a closer look and found that neighboring epithelial cells in K17 –/– embryos failed to enlarge in response to injury. Cultured K17 –/– keratinocytes were smaller than wild-type cells and showed slower rates of peptide chain elongation and of amino acid incorporation into protein. K17 –/– keratinocytes also showed decreased activity of Akt and mammalian target of rapamycin (mTOR), components of a pathway that regulates protein synthesis and thereby cell growth, but not of phosphatidylinositol 3-kinase (PI3K, which acts upstream of mTOR in growth factor signaling). The mTOR inhibitor rapamycin had less effect on translation in K17 –/– than in wild-type keratinocytes, and both stimulation of protein synthesis in response to serum (which contains growth factors) and mTOR activation were blunted. K17 bound to 14-3-3σ and serum promoted 14-3-3 movement into the cytoplasm of wild-type but not K17 –/– keratinocytes (in which 14-3-3 preferentially localized to the nucleus). Transfection of K17 –/– keratinocytes with wild-type K17 increased cytoplasmic 14-3-3 content, Akt and mTOR activity, protein synthesis, and cell size, whereas a form of K17 in which 14-3-3 binding sites were mutated did not rescue these defects. Thus, K17 appears not only to play a structural role but also to help regulate epithelial cell growth. S. Kim, P. Wong, P. A. Coulombe, A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature 441 , 362-365 (2006). [PubMed] M. B. Omary, N.-O. Ku, Skin care by keratins. Nature 441 , 296-297 (2006). [PubMed]