Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Cell Biology, Nencki Institute of Experimental Biology, 02-093 Warszawa, Poland.
Cell Rep. 2014 Jan 16;6(1):168-181. doi: 10.1016/j.celrep.2013.12.003. Epub 2013 Dec 27.
Gli proteins are transcriptional effectors of the Hedgehog (Hh) pathway in both normal development and cancer. We describe a program of multisite phosphorylation that regulates the conversion of Gli proteins into transcriptional activators. In the absence of Hh ligands, Gli activity is restrained by the direct phosphorylation of six conserved serine residues by protein kinase A (PKA), a master negative regulator of the Hh pathway. Activation of signaling leads to a global remodeling of the Gli phosphorylation landscape: the PKA target sites become dephosphorylated, while a second cluster of sites undergoes phosphorylation. The pattern of Gli phosphorylation can regulate Gli transcriptional activity in a graded fashion, suggesting a phosphorylation-based mechanism for how a gradient of Hh signaling in a morphogenetic field can be converted into a gradient of transcriptional activity.
Gli 蛋白是 Hedgehog（Hh）通路在正常发育和癌症中的转录效应因子。我们描述了一个多部位磷酸化程序，该程序调节 Gli 蛋白向转录激活剂的转化。在没有 Hh 配体的情况下，蛋白激酶 A（PKA）通过直接磷酸化六个保守丝氨酸残基来限制 Gli 活性，PKA 是 Hh 通路的主要负调控因子。信号的激活导致 Gli 磷酸化景观的全面重塑：PKA 的靶位点去磷酸化，而第二个位点簇发生磷酸化。Gli 磷酸化的模式可以以分级的方式调节 Gli 的转录活性，这表明一种基于磷酸化的机制，即形态发生场中 Hh 信号的梯度可以转化为转录活性的梯度。
