title: The energy sensor AMPK regulates Hedgehog signaling in human cells through a unique Gli1 metabolic checkpoint.
abstract: Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs) and its aberrant activation is a leading cause of Medulloblastoma, the most frequent pediatric brain tumor. We show here that the energy sensor AMPK inhibits Hh signaling by phosphorylating a single residue of human Gli1 that is not conserved in other species. Studies with selective agonists and genetic deletion have revealed that AMPK activation inhibits canonical Hh signaling in human, but not in mouse cells. Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation. Notably, we show that selective AMPK activation inhibits Gli1-driven proliferation and that this effect is linked to Ser408 phosphorylation, which represents a key metabolic checkpoint for Hh signaling. Collectively, this data unveil a novel mechanism of inhibition of Gli1 function, which is exclusive for human cells and may be exploited for the treatment of Medulloblastoma or other Gli1 driven tumors.
authors: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Roma, Italy.
authors: Laura
authors: L
authors: Di Magno
authors: Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors: Alessio
authors: A
authors: Basile
authors: Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors: Sonia
authors: S
authors: Coni
authors: Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors: Simona
authors: S
authors: Manni
authors: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Roma, Italy.
authors: Giulia
authors: G
authors: Sdruscia
authors: Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors: Davide
authors: D
authors: D'Amico
authors: Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors: Laura
authors: L
authors: Antonucci
authors: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Roma, Italy.
authors: Paola
authors: P
authors: Infante
authors: Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors: Enrico
authors: E
authors: De Smaele
authors: Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors: Danilo
authors: D
authors: Cucchi
authors: Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors: Elisabetta
authors: E
authors: Ferretti
authors: Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.|Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Roma, Italy.|Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, 00161 Rome, Italy.
authors: Lucia
authors: L
authors: Di Marcotullio
authors: Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.|Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Roma, Italy.|Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, 00161 Rome, Italy.
authors: Isabella
authors: I
authors: Screpanti
authors: Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.|Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, 00161 Rome, Italy.
authors: Gianluca
authors: G
authors: Canettieri
mesh_terms: D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000473:pathology*; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000473:pathology*; D051379:Mice; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism*
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D034741:RNA, Small Interfering; C509239:SHH protein, human; D000071676:Zinc Finger Protein GLI1; C526181:PRKAA2 protein, human; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human
keywords: AMPK; Gli1; Hedgehog; cancer metabolism; phosphorylation