Illuminating the function of the understudied kinase DYRK2 in ciliary Hedgehog signal transduction

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ABSTRACT We defined the proteomes of cilia from diverse organisms, including sea urchins and sea anemones and identified DYRK2, a poorly studied kinase not been previously implicated in ciliary biology. Subsequent study confirmed that DYRK2 localizes to cilia and revealed that loss of DYRK2 disrupts ciliary morphology. We also found that DYRK2 participates in ciliary Hedgehog signal transduction, communicating between Smoothened and GLI transcription factors, two central components of the pathway. Mutation of mouse Dyrk2 resulted in skeletal defects reminiscent of those caused by loss of Indian hedgehog. Like Dyrk2 mutations, pharmacological inhibition of DYRK2 dysregulated ciliary length control and attenuated Hedgehog signaling. In this pilot project, we will examine the molecular mechanisms by which DYRK2 functions in ciliary morphology, Hedgehog signaling, skeletal development and cancer. More specifically, we will investigate how DYRK2 acts downstream of Smoothened to transduce Hedgehog signals (Aim 1), how DYRK2 functions in skeletal development (Aim 2), and whether pharmacological inhibition of DYRK2 may be a tractable therapy for Hedgehog pathway-associated cancers (Aim 3). The proposed experiments use a combination of mammalian genetic, cell biological, imaging and biochemical approaches to reveal how DYRK2 functions in ciliary Hedgehog signal transduction, both in development and disease.