Crosstalk of Hedgehog and mTORC1 Pathways

Abstract

Hedgehog (Hh) signaling and mTOR signaling, essential for embryonic development and cellular metabolism, are both coordinated by the primary cilium. Observations from cancer cells strongly indicate crosstalk between Hh and mTOR signaling. This hypothesis is supported by several studies: Evidence points to a TGFβ-mediated crosstalk; Increased PI3K/AKT/mTOR activity leads to increased Hh signaling through regulation of the GLI transcription factors; increased Hh signaling regulates mTORC1 activity positively by upregulating NKX2.2, leading to downregulation of negative mTOR regulators; GSK3 and AMPK are, as members of both signaling pathways, potentially important links between Hh and mTORC1 signaling; The kinase DYRK2 regulates Hh positively and mTORC1 signaling negatively. In contrast, both positive and negative regulation of Hh has been observed for DYRK1A and DYRK1B, which both regulate mTORC1 signaling positively. Based on crosstalk observed between cilia, Hh, and mTORC1, we suggest that the interaction between Hh and mTORC1 is more widespread than it appears from our current knowledge. Although many studies focusing on crosstalk have been carried out, contradictory observations appear and the interplay involving multiple partners is far from solved.

Inhibition of the sonic hedgehog pathway activates TGF-β-activated kinase (TAK1) to induce autophagy and suppress apoptosis in thyroid tumor cells

“…Gli1 is a transcription factor that plays a central role in executing many biological functions of the Shh pathway 7 , 8 . Here we investigated the role of Gli1 in mediating GANT61-induced autophagy.…”

“…The Shh pathway is also highly activated in various tumor types ranging from extremely malignant pancreatic and lung cancers to the relatively benign well differentiated thyroid cancer. The Shh pathway can be cross-activated by the phosphatidylinositol-3 (PI)-3 and mitogen-activated protein (MAP) kinase pathways, and through paracrine activation by Shh-secreting tumor stromal cells 7 , 8 . Targeting the Shh pathway is a potential novel therapeutic strategy to treat cancers 6 .…”

BBS Proteins Affect Ciliogenesis and Are Essential for Hedgehog Signaling, but Not for Formation of iPSC-Derived RPE-65 Expressing RPE-Like Cells

“…In the lack of a functional BBSome-BBS17-BBS19-IFT25 transport system, it is likely that both PTCH1, SMO and GPR161 accumulate in the primary cilia because none of the proteins can be removed. SMO (and PTCH1) undergoes lateral transport in and out of primary cilia at steady-state, and if export is hampered, this might lead to accumulation in the primary cilia [ 25 , 31 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ]. BBS1 and BBS5 are both members of the BBSome, whereas BBS10 is a member of the BBS-chaperonin complex.…”

Signaling Pathway Mediating Myeloma Cell Growth and Survival

“…The autophagic pathway and the proteasome pathway regulate the degradation of intracellular proteins in MM. Recent studies show that Akt regulates downstream mTOR (mammalian target of rapamycin) and autophagy via the tuberous sclerosis 2 (TSC) 1/2 complex [ 80 , 81 ]. Therefore, inhibition of Akt or mTORC1 triggers autophagy.…”