Waschek James A, Dicicco-Bloom Emanuel, Nicot Arnaud, Lelievre Vincent
Mental Retardation Research Center, Semel Institute for Neuroscience, Jonsson Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, California 90095, USA.
Ann N Y Acad Sci. 2006 Jul;1070:120-8. doi: 10.1196/annals.1317.089.
Hedgehog (HH) is a secreted protein named for the bristle phenotype observed in Drosophila embryos that lack the corresponding gene. Three homologs have been characterized in vertebrates, all which have critical roles in the development of multiple organ systems. Moreover, these proteins regulate stem cell production and activation during tissue repair after injury, and appear to drive proliferation in a variety of type of tumors, including those arising in the brain, foregut, lung, breast, pancreas, stomach, and prostate. Early evidence from Drosophila, and later work in vertebrates established the cAMP/protein kinase A (PKA) pathway as a major pathway which opposes HH signaling, doing so by phosphorylating intracellular signaling mediators and targeting them for degradation. Thus, it seems possible that ligands which activate G protein-coupled receptors (GPCR) may act in some cases to oppose or enhance HH signaling. We studied a possible interaction of pituitary adenylyl cyclase-activating peptide (PACAP) with sonic hedgehog (SHH) in the developing cerebellum, where both PACAP and SHH are know to act. PACAP and the PAC1-specific agonist, maxadilan, were found to completely block the proliferative action of SHH on developing cerebellar granule neurons. It remains to be determined if HH/GPCR antagonistic interactions play additional important roles in development, plasticity, tissue repair, cancer, and other processes.
刺猬因子（HH）是一种分泌蛋白，因其在缺乏相应基因的果蝇胚胎中观察到的刚毛表型而得名。在脊椎动物中已鉴定出三种同源物，它们在多个器官系统的发育中均起关键作用。此外，这些蛋白在损伤后组织修复过程中调节干细胞的产生和激活，并且似乎在多种类型的肿瘤（包括发生在脑、前肠、肺、乳腺、胰腺、胃和前列腺的肿瘤）中驱动细胞增殖。来自果蝇的早期证据以及后来在脊椎动物中的研究确立了环磷酸腺苷/蛋白激酶A（PKA）途径是对抗HH信号的主要途径，其通过磷酸化细胞内信号介质并将其靶向降解来实现。因此，在某些情况下，激活G蛋白偶联受体（GPCR）的配体可能起到对抗或增强HH信号的作用。我们研究了垂体腺苷酸环化酶激活肽（PACAP）与音猬因子（SHH）在发育中的小脑中可能的相互作用，已知PACAP和SHH在小脑中均有作用。发现PACAP和PAC1特异性激动剂马克西迪兰完全阻断了SHH对发育中小脑颗粒神经元的增殖作用。HH/GPCR拮抗相互作用是否在发育、可塑性、组织修复、癌症和其他过程中发挥额外的重要作用仍有待确定。
