DYRK1B blocks canonical and promotes non-canonical Hedgehog signaling through activation of the mTOR/AKT pathway

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.

Systematic Elucidation and Validation of OncoProtein-Centric Molecular Interaction Maps

“…A number of studies have identified DYRK1B as a downstream effector of oncogenic KRAS 80,81 . However, in support of our prediction, other studies have reported that DYRK1B may function as an upstream regulator of KRAS through its modulation of the mTOR/AKT and MAPK pathways 83 . Oncogenic KRAS promotes hedgehog (HH) signaling 84 , and HH signaling induces DYRK1B expression, which results in the activation of mTOR/AKT signaling 83 .…”

“…As depicted in Figure 6, the dual specificity tyrosine phosphorylated kinase DYRK1B (gray oval) is predicted to aberrantly regulate KRAS. The connection between DYRK1B and KRAS signaling is established 54 but poorly understood [80][81][82][83] . A number of studies have identified DYRK1B as a downstream effector of oncogenic KRAS 80,81 .…”

A wake‐up call to quiescent cancer cells – potential use of DYRK1B inhibitors in cancer therapy

“…In many cancer cell lines, depletion of DYRK1B impairs cell survival and induces apoptosis, concomitant with increased intracellular levels of ROS and phosphorylation of histone 2AX on Ser139, which indicates DNA damage (Table 1). DYRK1B upregulates Increased ROS levels and increased DNA damage [12,53] EHT [68], Ro [53] Reduced growth and increased apoptosis of spheroid cells [39] EHT [68] Sensitization to mTOR inhibition [39] Ro [68], EHT [69], AZ [40] Reduced size of Panc1 and L3.6pl xenografts [39] EHT a [68], DYRKi b [39] Ovarian cancer SKOV3, TOV21G, OVCAR3, OVCAR5, OVCAR8, Hey, and primary cell lines…”

“…Increased cell cycle entry Ro [52] Increased apoptosis [28], [34] Ro [52] Increased ROS levels and increased DNA damage [28] Ro [52], EHT [50] Sensitization to cisplatin or carboplatin toxicity [28], [34] EHT [50] Sensitization to mTOR inhibition EHT [69], AZ [40] Reduced viability and increased apoptosis of spheroid cells [51] EHT [50], Ha, INDY [51] Lung cancer (NSCL) A549, H1299, H292 the expression of several antioxidant genes, including ferroxidase and superoxide dismutases 2 and 3 (SOD2, SOD3) [12,13,28]. Of note, cancer cells maintain higher ROS levels than normal cells and might thus be more sensitive to further accumulation of ROS [29].…”

Mutations in the sonic hedgehog pathway cause macrocephaly‐associated conditions due to crosstalk to the PI3K/AKT/mTOR pathway

“…It has been previously reported that SHH overexpression activates PI3K/mTOR signaling via the DYRK1B kinase (Singh, Dhanyamraju, & Lauth, ). Here, we demonstrate that loss of negative regulators of Hh pathway signaling is sufficient to activate PI3K/mTOR signaling.…”