The energy sensor AMPK regulates Hedgehog signaling in human cells through a
unique Gli1 metabolic checkpoint
#MMPMID26843621
Di Magno L
; Basile A
; Coni S
; Manni S
; Sdruscia G
; D'Amico D
; Antonucci L
; Infante P
; De Smaele E
; Cucchi D
; Ferretti E
; Di Marcotullio L
; Screpanti I
; Canettieri G
Oncotarget
2016[Feb]; 7
(8
): 9538-49
PMID26843621
show ga
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.
|3T3 Cells
[MESH]
|AMP-Activated Protein Kinases/genetics/*metabolism
[MESH]
free
free
free
