Plk1 kinase negatively regulates the Hedgehog signaling pathway by phosphorylating Gli1

Abstract

The Hedgehog (Hh) signaling is a highly conserved cell signaling pathway important for cell life, development and tumorigenesis. Increasing evidence suggests that Hh signaling pathway functions in certain phases of the cell cycle. However, the coordination between Hh signaling and cell cycle control remains poorly understood. Here, we show that polo-like kinase-1 (Plk1), a critical protein kinase regulating many processes during the cell cycle, also regulates Hh signaling by phosphorylating and inhibiting Gli1, a downstream transcription factor of Hh signaling pathway. Gli1 expression increases along with Hh signaling activation, leading to up-regulation of Hh target genes, including Cyclin E, during the G1 and S phases. Gli1 is phosphorylated at S481 by Plk1 and this phosphorylation facilitates the nuclear export and binding of Gli1 with its negative regulator Sufu, leading to a reduction in Hh signaling activity. Inhibition of Plk1 kinase activity maintained the function of Gli1 for its downstream gene expression. Collectively, our data reveal a novel mechanism regarding the crosstalk between Hh signaling and cell cycle control.