The Role of 14-3-3 eta in EGF-induced Skin Cell Transformation

Abstract

14-3-3 proteins are evolutionarily conserved, acidic 28-30-kDa proteins of seven isoforms (β, γ, ε, ζ, η, σ, and τ) in mammals. 14-3-3s act as adaptor proteins that control the function of their target proteins through highly regulated protein-protein interactions. Recently, some of 14-3-3 isoforms were suggested to be tumor-suppressing or promoting, but the role of 14-3-3s in skin carcinogenesis has not yet been elucidated. Here, I suggest that 14-3-3 η is involved in epidermal growth factor (EGF)-induced skin cell transformation. First, it was shown that knockdown of 14-3-3 η efficiently suppressed anchorage-independent HaCaT cell transformation and proliferation induced by EGF compared with control si- or sh-mock cells. Moreover, knockdown of 14-3-3 η inhibited phosphorylation of CREB upon EGF stimulation followed by reduction of c-Fos expression. Furthermore, I investigated the molecular mechanisms underlying the involvement of 14-3-3 η in EGF-induced skin cell transformation. I found direct physical interaction of 14-3-3 η with RSK2, a critical factor in EGF-induced skin cell transformation and direct kinase of CREB. In addition, I identified that four serine residues (Ser160, Ser386, Ser415, and Ser635) of RSK2 were crucial for the physical binding with 14-3-3 η. Taken together, I suggest that 14-3-3 η might have a role as a tumor enhancer in EGF-induced skin cell transformation, via direct interaction with RSK2.