Abstract
Hedgehog (Hh) signaling plays a pivotal role in animal development and its deregulation in humans causes birth defects and several types of cancer. Protein Kinase A (PKA) modulates Hh signaling activity through phosphorylating the transcription factor Cubitus interruptus (Ci) and G protein coupled receptor (GPCR) family protein Smoothened (Smo) in Drosophila, but how PKA activity is regulated remains elusive. Here, we identify a novel regulator of the Hh pathway, the capping-enzyme mRNA-cap, which positively regulates Hh signaling activity through modulating PKA activity. We provide genetic and biochemical evidence that mRNA-cap inhibits PKA kinase activity to promote Hh signaling. Interestingly, regulation of Hh signaling by mRNA-cap depends on its cytoplasmic capping-enzyme activity. In addition, we show that the mammalian homolog of mRNA-cap, RNGTT, can replace mRNA-cap to play the same function in the Drosophila Hh pathway and that knockdown of Rngtt in cultured mammalian cells compromised Shh pathway activity, suggesting that RNGTT is functionally conserved. Our study makes an unexpected link between the mRNA capping machinery and the Hh signaling pathway, unveils a new facet of Hh signaling regulation, and reveals a potential drug target for modulating Hh signaling activity.
Highlights
Hedgehog (Hh) signaling plays a pivotal role in animal development and its deregulation in humans causes birth defects and several types of cancer
Given that Hh pathway plays an important role in wing development and its deregulation causes wing development defect, we sought to identify novel regulators of Hh signaling via analyzing wing phenotypes caused by either loss or gain of function of such regulators
Through co-expressing the transgene and the RNAi line, we found that mRNA-cap transgenic expression could rescue the RNAi-induced abnormal wing phenotype (Fig. 1C), suggesting that the aberrant wing phenotype is caused by loss of mRNA-cap
Summary
Hedgehog (Hh) signaling plays a pivotal role in animal development and its deregulation in humans causes birth defects and several types of cancer. Activated Smo recruits the kinesin-like protein Costal[2] (Cos2) and the Ser/ Thr kinase Fused (Fu) to trigger the activation of latent transcription factor Cubitus interruptus (Ci)[15,16,17,18,19,20,21,22], which enters the nucleus to turn on the expression of Hh target genes including decapentaplegic (dpp), patched (ptc) and engrailed (en)[1, 23, 24]. PKA plays a dual role in the Hh pathway by activating Smo but inhibiting Ci depending on the availability of the Hh ligand. Despite its dual role in Hh signaling, loss of PKA results in Hh pathway activation instead of inhibition due to the depression of Ci: loss of CiR and accumulation of CiF, some of which is converted into CiA 24, 42
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