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Cell Rep. 2014 Jan 16;6(1):168-181. doi: 10.1016/j.celrep.2013.12.003. Epub 2013 Dec 27.

Gli protein activity is controlled by multisite phosphorylation in vertebrate Hedgehog signaling.

Author information

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.
Department of Neurobiology, Eli and Edythe Broad Stem Cell Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Department of Biochemistry, and Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Laboratory of Quantitative Systems Analysis, Leibniz-Institute for Analytical Sciences - ISAS - e.V., 44227 Dortmund, Germany.
Contributed equally


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.

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