Expression and localization of Ski determine cell type–specific TGFβ signaling effects on the cell cycle

Abstract

Transforming growth factor β (TGFβ) promotes epithelial cell differentiation but induces Schwann cell proliferation. We show that the protooncogene Ski (Sloan-Kettering viral oncogene homologue) is an important regulator of these effects. TGFβ down-regulates Ski in epithelial cells but not in Schwann cells. In Schwann cells but not in epithelial cells, retinoblastoma protein (Rb) is up-regulated by TGFβ. Additionally, both Ski and Rb move to the cytoplasm, where they partially colocalize. In vivo, Ski and phospho-Rb (pRb) appear to interact in the Schwann cell cytoplasm of developing sciatic nerves. Ski overexpression induces Rb hyperphosphorylation, proliferation, and colocalization of both proteins in Schwann cell and epithelial cell cytoplasms independently of TGFβ treatment. Conversely, Ski knockdown in Schwann cells blocks TGFβ-induced proliferation and pRb cytoplasmic relocalization. Our findings reveal a critical function of fine-tuned Ski levels in the control of TGFβ effects on the cell cycle and suggest that at least a part of Ski regulatory effects on TGFβ-induced proliferation of Schwann cells is caused by its concerted action with Rb.