Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling

Abstract

Hedgehogs (Hhs) are key signaling regulators of stem cell maintenance and tissue patterning in embryos, and activating mutations in the pathway that increase Gli transcriptional activity are causal in a diversity of cancers. Here, we report that phosphoinositide 3-kinase (PI3-kinase)-dependent Akt activation is essential for Sonic Hedgehog (Shh) signaling in the specification of neuronal fates in chicken neural explants, chondrogenic differentiation of 10T1/2 cells, and Gli activation in NIH 3T3 cells. Stimulation of PI3-kinase/Akt by insulin-like growth factor I potentiates Gli activation induced by low levels of Shh; however, insulin-like growth factor I alone is insufficient to induce Gli-dependent transcription. Protein kinase A (PKA) and glycogen synthase kinase 3β sequentially phosphorylate Gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity. Gli2 mutant proteins in which the major PKA and glycogen synthase kinase 3β phosphorylation sites were mutated to alanine remain fully transcriptionally active; however, PKA-mutant Gli2 functions independently of Akt signaling, indicating that Akt positively regulates Shh signaling by controlling PKA-mediated Gli inactivation. Our findings provide a basis for the synergistic role of PI3-kinase/Akt in Hh signaling in embryonic development and Hh-dependent tumors.

Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2

“…S166 and S186 are known to be phosphorylated by Akt, which activates the Mdm2-mediated degradation of p53 (22,23). Recently, it was reported that Smo activates phosphoinositide 3-kinase (PI3K) and Akt, both of which belong to an essential Shh signaling pathway (24). As shown in Fig.…”

Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells

“…We reported that EGF also increases Shh mRNA levels in primary HSC [58]. Evidence that two different growth factors that activate AKT in HSC induce HSC expression of Shh is intriguing because insulin like growth factor (IGF)1 cooperates with Shh to activate AKT-dependent post-translational mechanisms that stabilize Gli2 in Hhresponsive C3H101/2 cells [59]. Thus, there is growing evidence that Hh signaling modulates growth factor actions (and vice versa) in Hh responsive cells.…”

Accumulation of Hedgehog-Responsive Progenitors Parallels Alcoholic Liver Disease Severity in Mice and Humans

“…Fatty liver disease was accompanied by increased hepatic expression of both Sonic hedgehog (Shh) ligand ( Figure 2A) and several Hh target genes, including the Hh receptor, patched (Ptc, Figure 2B), Gli-2, an Hh-regulated transcription factor ( Figure 2C), 29 and Frizzled related peptide (Frp)-1, a soluble inhibitor of canonical Wnt signaling ( Figure 2D). 30 Interestingly, induction of Sonic hedgehog ligand and the Hh signaling components Ptc and Gli-2 was greater in EtOH-fed mice than HF controls, whereas EtOH consumption did not potentiate HF diet-associated increases in Frp-1.…”