Decoding the phosphorylation code in Hedgehog signal transduction.
Decoding the phosphorylation code in Hedgehog signal transduction.
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解码 Hedgehog 信号转导中的磷酸化密码
作者：
Hedgehog（Hh）信号在胚胎发育和成体组织稳态中起着关键作用，其失调导致包括癌症在内的许多人类疾病。Hh与十二跨膜蛋白Patched（Ptc）的结合增强了其对Smoothened（Smo）的抑制，Smo是与G蛋白偶联受体（GPCR）相关的七跨膜蛋白，导致Smo磷酸化和活化。Smo通过细胞内信号复合物将潜在转录因子Cubitus interruptus（Ci）/Gli从截短的阻遏物转化为全长激活物，导致Hh靶基因的去阻遏/激活。越来越多的证据表明，磷酸化参与了从Smo到Ci/Gli的信号传递中的几乎每一步，并且几个关键途径组分的差异磷酸化可能对于将Hh形态发生蛋白梯度转化为分级途径活性至关重要。本文综述了磷酸化在Hh信号转导中的多方面作用，并讨论了果蝇和哺乳动物Hh信号转导机制的保守性和差异。
Hedgehog (Hh) signaling plays pivotal roles in embryonic development and adult tissue homeostasis, and its deregulation leads to numerous human disorders including cancer. Binding of Hh to Patched (Ptc), a twelve-transmembrane protein, alleviates its inhibition of Smoothened (Smo), a seven-transmembrane protein related to G-protein-coupled receptors (GPCRs), leading to Smo phosphorylation and activation. Smo acts through intracellular signaling complexes to convert the latent transcription factor Cubitus interruptus (Ci)/Gli from a truncated repressor to a full-length activator, leading to derepression/activation of Hh target genes. Increasing evidence suggests that phosphorylation participates in almost every step in the signal relay from Smo to Ci/Gli, and that differential phosphorylation of several key pathway components may be crucial for translating the Hh morphogen gradient into graded pathway activities. In this review, we focus on the multifaceted roles that phosphorylation plays in Hh signal transduction, and discuss the conservation and difference between Drosophila and mammalian Hh signaling mechanisms.
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