Interaction of PACAP with Sonic hedgehog reveals complex regulation of the Hedgehog pathway by PKA
Interaction of PACAP with Sonic hedgehog reveals complex regulation of the Hedgehog pathway by PKA
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DOI：
10.1016/j.cellsig.2013.07.012
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发表时间：
2013-11-01
影响因子：
4.8
通讯作者：
Waschek, James A.
中科院分区：
文献类型：
--
作者：
Niewiadomski, Pawel;Zhujiang, Annie;Waschek, James A.
Sonic hedgehog （Shh）信号对于小脑颗粒细胞祖细胞（cGCPs）的增殖至关重要，其异常激活可导致小脑癌成神经管细胞瘤。垂体腺苷酸环化酶激活多肽（PACAP）抑制shh驱动的cGCPs增殖，并在小鼠髓母细胞瘤中发挥抑瘤作用。我们发现PACAP通过激活蛋白激酶a （PKA）和抑制sh依赖性转录因子Gli2易位到初级纤毛的机制来阻断典型的Shh信号。研究表明，在缺乏Shh的情况下，PICA在抑制基因转录方面发挥了重要作用，但发现全球PICA活性水平不能很好地预测Shh通路激活的程度。我们提出核心Shh通路调节初级纤毛附近的一个小区隔池。影响全局PICA活性水平的GPCRs，如PACAP受体，与典型的Shh信号合作，通过PICA调节Gli蛋白磷酸化。这种相互作用有助于微调Shh通路的转录和生理功能。(C) 2013年作者。Elsevier Inc版权所有。
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. PICA is shown to play an essential role in inhibiting gene transcription in the absence of Shh, but global PICA 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 PICA in the vicinity of primary cilia. GPCRs that affect global PICA activity levels, such as the PACAP receptor, cooperate with the canonical Shh signal to regulate Gli protein phosphorylation by PICA. This interaction serves to fine-tune the transcriptional and physiological function of the Shh pathway. (C) 2013 The Authors. Published by Elsevier Inc All rights reserved.