Type I Keratin 17 Protein Is Phosphorylated on Serine 44 by p90 Ribosomal Protein S6 Kinase 1 (RSK1) in a Growth- and Stress-dependent Fashion

• Published in: The Journal of biological chemistry 2011-12, Vol.286 (49), p.42403-42413
• Main Authors: Pan, Xiaoou, Kane, Lesley A., Van Eyk, Jennifer E., Coulombe, Pierre A.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Apoptosis; Biomarkers - metabolism; Cell Biology; Cell Growth; Cell Proliferation; Cell Stress; ERK; Extracellular Signal-Regulated MAP Kinases - metabolism; HeLa Cells; Humans; Intermediate Filaments; Keratin 17; Keratin-17 - metabolism; Keratinocytes; Keratinocytes - cytology; Keratinocytes - metabolism; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Phosphorylation; Protein Kinase C (PKC); Protein Kinase C - metabolism; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; RSK; Sequence Homology, Amino Acid; Serine - chemistry; Skin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.302042

Keratin 17 (K17) is a type I intermediate filament protein that is constitutively expressed in ectoderm-derived epithelial appendages and robustly induced in epidermis following injury, during inflammation, and in chronic diseases such as psoriasis and cancer. Mutations within K17 are responsible for two rare diseases related to ectodermal dysplasias. Studies in K17-null mice uncovered several roles for K17, including structural support, resistance to TNFα-induced apoptosis, regulation of protein synthesis, and modulation of cytokine expression. Yet, little is known about the regulation of K17 protein via post-translational modification. Here, we report that serine 44 in the N-terminal head domain of K17 (K17-Ser44) is phosphorylated in response to extracellular stimuli (serum, EGF, and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate) that alter skin keratinocyte growth, and to cellular stresses (sorbitol-induced hyperosmotic shock, UV irradiation, and hydrogen peroxide-induced oxidative stress). It also occurs in basaloid skin tumors in situ. Upon its stimulation in skin keratinocytes, K17-Ser44 phosphorylation is induced rapidly but stays on transiently. The majority of the phosphorylated K17-Ser44 pool is polymer-bound and is not obviously related to a change in filament organization. The amino acid sequence surrounding K17-Ser44 matches the consensus for the AGC family of basophilic kinases. We show that p90 RSK1, an AGC kinase involved in the regulation of cell survival and proliferation, phosphorylates K17-Ser44 in skin keratinocytes. These findings confirm and expand the tight link that has emerged between K17 up-regulation and growth and stress responses in the skin epithelium. Background: Keratin 17 (K17) provides structural support and regulates cell growth, apoptosis, and immune responses in skin epithelia. Results: K17-Ser44 is dynamically phosphorylated by RSK1 in skin keratinocytes undergoing growth or stress. Conclusion: K17 is regulated by Ser44 phosphorylation in vivo. Significance: K17-Ser44 phosphorylation provides a novel biomarker reflecting growth or stress situations in keratinocytes.