Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling.
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 3beta 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 3beta 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.
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, 1157 BRBII/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Natalia A
NA
Riobó
Ke
K
Lu
Xingbin
X
Ai
Gwendolyn M
GM
Haines
Charles P
CP
Emerson
D000818:Animals; D002454:Cell Differentiation; D002645:Chickens; D020219:Chondrogenesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D047108:Embryonic Development; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D053823:Hedgehog Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D053823:Hedgehog Proteins; D007334:Insulin-Like Growth Factor I; D051741:Kruppel-Like Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse; C000605507:Gsk3b protein, mouse