Abstract
Hedgehog (Hh) signaling plays important roles in embryonic development and in tumor formation. Apart from the well-established stimulation of the GLI family of transcription factors, Hh ligands promote the phosphorylation and activation of mTOR and AKT kinases, yet the molecular mechanism underlying these processes are unknown. Here, we identify the DYRK1B kinase as a mediator between Hh signaling and mTOR/AKT activation. In fibroblasts, Hh signaling induces DYRK1B protein expression, resulting in activation of the mTOR/AKT kinase signaling arm. Furthermore, DYRK1B exerts positive and negative feedback regulation on the Hh pathway itself: It negatively interferes with SMO-elicited canonical Hh signaling, while at the same time it provides positive feed-forward functions by promoting AKT-mediated GLI stability. Due to the fact that the mTOR/AKT pathway is itself subject to strong negative feedback regulation, pharmacological inhibition of DYRK1B results in initial upregulation followed by downregulation of AKT phosphorylation and GLI stabilization. Addressing this issue therapeutically, we show that a pharmacological approach combining a DYRK1B antagonist with an mTOR/AKT inhibitor results in strong GLI1 targeting and in pronounced cytotoxicity in human pancreatic and ovarian cancer cells.
Highlights
Hedgehog (Hh) signaling is an important regulatory system in embryonic development, stem cell biology and tumorigenesis [1,2,3]
The underlying mechanism of this negative regulation requires further investigations. 2.) In contrast, overexpressed DYRK1B enhanced the protein stability of GLI1 by preventing its proteasomal degradation. This stabilizing effect is most likely executed through AKT, which we found to be activated by DYRK1B and which is known to phosphorylate and protect GLI transcription factors from decay [7, 26]
The exact mechanism of AKT stimulation by DYRK1B is currently unknown and requires www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget future work. 3.) Because of DYRK1B’s ability to activate the PI3K/mTOR/AKT pathway, the whole DYRK1B-Hh/ GLI-system is subject to pronounced feedback control, resulting in a strong influence of kinetics on the actual Hh pathway output
Summary
Hedgehog (Hh) signaling is an important regulatory system in embryonic development, stem cell biology and tumorigenesis [1,2,3]. Well-established target genes include e.g. PTCH1 and GLI1, which regulate the Hh pathway in a negative and positive manner, respectively, and are often utilized as surrogate read-outs for general pathway activity Such transcriptional feedback loops are frequently encountered in physiologically important signaling pathways and serve to fine-tune the entire system. Non-transcriptional regulatory inputs through e.g. kinases have been documented and it is well known that Hh signaling promotes the phosphorylation of e.g. MEK, ERK and AKT kinases [4,5,6,7] These mechanisms are often exploited in cancer cells in ‘non-canonical’ modes of signaling, leading to e.g. Hh ligand/receptor-independent activation of GLI transcription factors [8,9,10,11]
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