Intellectual Development and Disabilities Research Center, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell Signal. 2013 Nov;25(11):2222-30. doi: 10.1016/j.cellsig.2013.07.012. Epub 2013 Jul 18.
Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule cell progenitors (cGCPs) and its aberrant activation causes a cerebellar cancer medulloblastoma. Pituitary adenylate cyclase activating polypeptide (PACAP) inhibits Shh-driven proliferation of cGCPs and acts as tumor suppressor in murine medulloblastoma. We show that PACAP blocks canonical Shh signaling by a mechanism that involves activation of protein kinase A (PKA) and inhibition of the translocation of the Shh-dependent transcription factor Gli2 into the primary cilium. PKA is shown to play an essential role in inhibiting gene transcription in the absence of Shh, but global PKA activity levels are found to be a poor predictor of the degree of Shh pathway activation. We propose that the core Shh pathway regulates a small compartmentalized pool of PKA in the vicinity of primary cilia. GPCRs that affect global PKA activity levels, such as the PACAP receptor, cooperate with the canonical Shh signal to regulate Gli protein phosphorylation by PKA. This interaction serves to fine-tune the transcriptional and physiological function of the Shh pathway.
声波刺猬（Shh）信号对于小脑颗粒细胞前体细胞（cGCPs）的增殖是必不可少的，其异常激活会导致小脑癌症髓母细胞瘤。垂体腺苷酸环化酶激活肽（PACAP）抑制 Shh 驱动的 cGCP 增殖，并在鼠类髓母细胞瘤中作为肿瘤抑制因子发挥作用。我们表明，PACAP 通过一种涉及蛋白激酶 A（PKA）激活和抑制 Shh 依赖性转录因子 Gli2 向初级纤毛易位的机制来阻断经典的 Shh 信号。显示 PKA 在 Shh 不存在的情况下对于抑制基因转录起着至关重要的作用，但是全局 PKA 活性水平被发现是 Shh 途径激活程度的不良预测因子。我们提出核心 Shh 途径在初级纤毛附近调节 PKA 的一个小分隔池。影响全局 PKA 活性水平的 GPCR，如 PACAP 受体，与经典的 Shh 信号合作，通过 PKA 调节 Gli 蛋白磷酸化。这种相互作用有助于微调 Shh 途径的转录和生理功能。
