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

摘要 我们定义了来自不同生物体的纤毛蛋白质组，包括海胆和海葵， DYRK2是一种研究较少的激酶，以前未涉及纤毛生物学。后续研究 证实了DYRK2定位于纤毛，并揭示了DYRK2的缺失破坏纤毛形态。我们也 发现DYRK2参与睫状体Hedgehog信号转导，在Smoothened细胞之间进行通讯， 和GLI转录因子，这是该途径的两个中心组分。小鼠Dyrk 2突变导致 骨骼缺陷使人联想到那些由印度刺猬的损失造成的。与Dyrk2突变一样，药理学 抑制DYRK2失调的纤毛长度控制和减弱Hedgehog信号传导。 在这个试点项目中，我们将研究DYRK2在纤毛形态中发挥作用的分子机制， 刺猬信号，骨骼发育和癌症。更具体地说，我们将研究DYRK2是如何起作用的。 Smoothened到Hedgehog信号的下游（Aim 1），DYRK2如何在骨骼肌中发挥作用 发展（目的2），以及DYRK2的药理学抑制是否可能是一种易于治疗的治疗方法， Hedgehog通路相关癌症（Aim 3）。拟议的实验使用哺乳动物的组合， 遗传学、细胞生物学、成像和生物化学方法来揭示DYRK2在睫状刺猬中的功能 信号转导，无论是在发展和疾病。

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.