Phorbol esters inhibit the Hedgehog signalling pathway downstream of Suppressor of Fused, but upstream of Gli.
The developmentally important Hedgehog (Hh) signal transduction pathway, which has recently been implicated in several forms of cancer, is subject to regulation by several protein kinases. Here, we address the role of protein kinase Cdelta in pathway inhibition and show that cellular depletion or pharmacological inhibition of this kinase isoform results in a blockade of signalling between Suppressor of Fused and the Gli transcription factors. We further provide evidence that the observed pathway inhibition is independent of primary cilia and the mitogen-activated protein kinase kinase (Mek1) kinase. These findings allowed for the rapid dissection of downstream Hh pathway activation mechanisms in human tumour cells and demonstrate a surprising variation in how cells can activate signalling in a ligand- and receptor-independent manner.
Lauth
M
M
Department of Biosciences and Nutrition, Karolinska Institutet, Novum Research Park, Huddinge, Sweden. matthias.lauth@biosci.ki.se
Bergström
A
A
Toftgård
R
R
D000818:Animals; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D010703:Phorbol Esters; D012097:Repressor Proteins; C490763:Sufu protein, mouse; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D051745:Protein Kinase C-delta; D048369:MAP Kinase Kinase 1; D013755:Tetradecanoylphorbol Acetate