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Genetic and chemical studies towards the mechanistic understanding of Gli activation [electronic resource]

The activation of the Hedgehog (Hh) pathway leading to Gli-dependent transcription plays critical roles in tissue patterning, homeostasis, and transformation. Despite the initial discovery of the pathway 30 years ago, a complete mechanistic understanding of Hh signal transduction remains elusive. By conducting a genome-scale overexpression screen using mammalian open reading frames (ORFs), I have identified the Rho GAP domain-containing protein Arhgap36, the homeodomain-interacting protein kinase Hipk4, and MED26, a subunit of the Mediator complex, as regulators of Gli function. This study represents the first report describing a functional role of Arhgap36 in any signaling process, and demonstrates Hipk4 modulates the cellular response to Hh ligand. The activity of MED26 was revealed in the context of the small molecule Hedgehog Pathway Inihibitor-1 (HPI-1), giving further insight to its mechanism of action. In addition, we describe the relevant mechanism of action of the small molecule JK184, a microtubule-disrupting agent that can have both positive and negative effects on pathway activity, depending on the nature of pathway perturbation. These findings provide new insights into how cells regulate Gli-dependent transcription and suggest strategies for the therapeutic intervention of Hh pathway-dependent disease.