| Title: |
Calmodulin enhances mTORC1 signaling by preventing TSC2-Rheb binding. |
| Authors: |
Yuna Amemiya1, Yuichiro Ioi1, Makoto Araki2, Kenji Kontani2, Masatoshi Maki1, Hideki Shibata1, Terunao Takahara1 takahara@agr.nagoya-u.ac.jp |
| Source: |
Journal of Biological Chemistry. Feb2025, Vol. 301 Issue 2, p1-16. 16p. |
| Subject Terms: |
*CALCIUM ions, *TUBEROUS sclerosis, *INTRACELLULAR calcium, *BINDING site assay, *CELL growth |
| Abstract: |
The mechanistic target of rapamycin complex 1 (mTORC1) functions as a master regulator of cell growth and proliferation. We previously demonstrated that intracellular calcium ion (Ca2+) concentration modulates the mTORC1 pathway via binding of the Ca2+ sensor protein calmodulin (CaM) to tuberous sclerosis complex 2 (TSC2), a critical negative regulator of mTORC1. However, the precise molecular mechanism by which Ca2+/CaM modulates mTORC1 activity remains unclear. Here, we performed a binding assay based on nano-luciferase reconstitution, a method for detecting weak interactions between TSC2 and its target, Ras homolog enriched in the brain (Rheb), an activator of mTORC1. CaM inhibited the binding of TSC2 to Rheb in a Ca2+-dependent manner. Live-cell imaging analysis indicated increased interaction between the CaMbinding region of TSC2 and CaM in response to elevated intracellular Ca2+ levels. Furthermore, treatment with carbachol, an acetylcholine analog, elevated intracellular Ca2+ levels and activated mTORC1. Notably, carbachol-induced activation of mTORC1 was inhibited by CaM inhibitors, corroborating the role of Ca2+/CaM in promoting the mTORC1 pathway. Consistent with the effect of Ca2+/CaM on the TSC2-Rheb interaction, increased intracellular Ca2+ concentration promoted the dissociation of TSC2 from lysosomes without affecting Akt-dependent phosphorylation of TSC2, suggesting that the regulatory mechanism of TSC2 by Ca2+/CaM is distinct from the previously established action mechanism of TSC2. Collectively, our findings offer mechanistic insights into TSC2-Rheb regulation mediated by Ca2+/CaM, which links Ca2+ signaling to mTORC1 activation. [ABSTRACT FROM AUTHOR] |
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| Database: |
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