TY - JOUR
T1 - IGF/mTORC1/S6 Signaling Is Potentiated and Prolonged by Acute Loading of Subtoxicological Manganese Ion
AU - Tang, Xueqi
AU - Balachandran, Rekha C.
AU - Aschner, Michael
AU - Bowman, Aaron B.
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/8
Y1 - 2023/8
N2 - The insulin-like growth factor (IGF)/insulin signaling (IIS) pathway is involved in cellular responses against intracellular divalent manganese ion (Mn2+) accumulation. As a pathway where multiple nodes utilize Mn2+ as a metallic co-factor, how the IIS signaling patterns are affected by Mn2+ overload is unresolved. In our prior studies, acute Mn2+ exposure potentiated IIS kinase activity upon physiological-level stimulation, indicated by elevated phosphorylation of protein kinase B (PKB, also known as AKT). AKT phosphorylation is associated with IIS activity; and provides direct signaling transduction input for the mammalian target of rapamycin complex 1 (mTORC1) and its downstream target ribosomal protein S6 (S6). Here, to better define the impact of Mn2+ exposure on IIS function, Mn2+-induced IIS activation was evaluated with serial concentrations and temporal endpoints. In the wild-type murine striatal neuronal line STHdh, the acute treatment of Mn2+ with IGF induced a Mn2+ concentration-sensitive phosphorylation of S6 at Ser235/236 to as low as 5 μM extracellular Mn2+. This effect required both the essential amino acids and insulin receptor (IR)/IGF receptor (IGFR) signaling input. Similar to simultaneous stimulation of Mn2+ and IGF, when a steady-state elevation of Mn2+ was established via a 24-h pre-exposure, phosphorylation of S6 also displayed higher sensitivity to sub-cytotoxic Mn2+ when compared to AKT phosphorylation at Ser473. This indicates a synergistic effect of sub-cytotoxic Mn2+ on IIS and mTORC1 signaling. Furthermore, elevated intracellular Mn2+, with both durations, led to a prolonged activation in AKT and S6 upon stimulation. Our data demonstrate that the downstream regulator S6 is a highly sensitive target of elevated Mn2+ and is well below the established acute cytotoxicity thresholds (<50 μM). These findings indicate that the IIS/mTORC1 pathways, in which Mn2+ normally serves as an essential co-factor, are dually responsible for the cellular changes in exposures to real-world Mn2+ concentrations.
AB - The insulin-like growth factor (IGF)/insulin signaling (IIS) pathway is involved in cellular responses against intracellular divalent manganese ion (Mn2+) accumulation. As a pathway where multiple nodes utilize Mn2+ as a metallic co-factor, how the IIS signaling patterns are affected by Mn2+ overload is unresolved. In our prior studies, acute Mn2+ exposure potentiated IIS kinase activity upon physiological-level stimulation, indicated by elevated phosphorylation of protein kinase B (PKB, also known as AKT). AKT phosphorylation is associated with IIS activity; and provides direct signaling transduction input for the mammalian target of rapamycin complex 1 (mTORC1) and its downstream target ribosomal protein S6 (S6). Here, to better define the impact of Mn2+ exposure on IIS function, Mn2+-induced IIS activation was evaluated with serial concentrations and temporal endpoints. In the wild-type murine striatal neuronal line STHdh, the acute treatment of Mn2+ with IGF induced a Mn2+ concentration-sensitive phosphorylation of S6 at Ser235/236 to as low as 5 μM extracellular Mn2+. This effect required both the essential amino acids and insulin receptor (IR)/IGF receptor (IGFR) signaling input. Similar to simultaneous stimulation of Mn2+ and IGF, when a steady-state elevation of Mn2+ was established via a 24-h pre-exposure, phosphorylation of S6 also displayed higher sensitivity to sub-cytotoxic Mn2+ when compared to AKT phosphorylation at Ser473. This indicates a synergistic effect of sub-cytotoxic Mn2+ on IIS and mTORC1 signaling. Furthermore, elevated intracellular Mn2+, with both durations, led to a prolonged activation in AKT and S6 upon stimulation. Our data demonstrate that the downstream regulator S6 is a highly sensitive target of elevated Mn2+ and is well below the established acute cytotoxicity thresholds (<50 μM). These findings indicate that the IIS/mTORC1 pathways, in which Mn2+ normally serves as an essential co-factor, are dually responsible for the cellular changes in exposures to real-world Mn2+ concentrations.
KW - insulin-like growth factor/insulin signaling
KW - mammalian target of rapamycin complex 1
KW - manganese
KW - striatal neuronal cells
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U2 - 10.3390/biom13081229
DO - 10.3390/biom13081229
M3 - Article
C2 - 37627294
AN - SCOPUS:85168745264
SN - 2218-273X
VL - 13
JO - Biomolecules
JF - Biomolecules
IS - 8
M1 - 1229
ER -