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.
Highlights
Sonic Hedgehog (Shh) pathway is a critical regulator of embryonic development, cell proliferation and stem cell fate
To determine whether the intracellular energy sensing machinery and the developmental Hh signaling are functionally connected, we tested the effect of different AMP Kinase (AMPK) agonists in Hh-stimulated cells
The occurrence of resistance observed in patients treated with Smo antagonists has dampened the enthusiasm for this class of inhibitors and opened a new era of investigation, aimed at the identification of inhibitors acting at a downstream level
Summary
Sonic Hedgehog (Shh) pathway is a critical regulator of embryonic development, cell proliferation and stem cell fate. Shh signaling promotes postnatal proliferation of cerebellar granule cell progenitors (GCPs) [1], and its deregulation at this level causes Medulloblastoma (MB), the most frequent brain malignancy of the childhood [2, 3]. Shh ligand binds to the inhibitory receptor Patched (Ptch), relieving its inhibitory effect on the transmembrane transducer Smoothened (Smo). These events initiate a cascade of intracellular processes that lead to the activation of the Gli transcription factors (Gli, Gli and Gli). A key event for Gli activation is the dissociation from the cytoplasmic inhibitor Sufu [4].
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