The Hedgehog (Hh) pathway regulates cell differen- tiation and proliferation during development by controlling the Gli transcription factors. Cell fate de- cisions and progression toward organ and tissue maturity must be coordinated, and how an energy sensor regulates the Hh pathway is not clear. AMP- activated protein kinase (AMPK) is an important sensor of energy stores and controls protein synthe- sis and other energy-intensive processes. AMPK is directly responsive to intracellular AMP levels, inhib- iting a wide range of cell activities if ATP is low and AMP is high. Thus, AMPK can affect development by influencing protein synthesis and other processes needed for growth and differentiation. Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcrip- tional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency.
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Li YH, Luo J, Mosley YY, Hedrick VE, Paul LN, Chang J, Zhang G, Wang YK, Banko MR, Brunet A, Kuang S, Wu JL, Chang CJ, Scott MP, Yang JY. AMP-Activated Protein Kinase Directly Phosphorylates and Destabilizes Hedgehog Pathway Transcription Factor GLI1 in Medulloblastoma. Cell Rep. 2015 Jul 28;12(4):599-609. doi: 10.1016/j.celrep.2015.06.054. Epub 2015 Jul 16. PMID: 26190112; PMCID: PMC4521589.