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.