The Akt-Rheb-mTORC1 pathway plays a crucial role in regulating cell growth, but the mechanisms underlying the activation of Rheb-mTORC1 by Akt remain unclear. In our previous study, we found that CBAP was highly expressed in human T-ALL cells and primary tumors, and its deficiency led to reduced phosphorylation of TSC2/S6K1 signaling proteins as well as impaired cell proliferation and leukemogenicity. We also demonstrated that CBAP was required for Akt-mediated TSC2 phosphorylation in vitro. In response to insulin, CBAP was also necessary for the phosphorylation of TSC2/S6K1 and the dissociation of TSC2 from the lysosomal membrane. Here we report that CBAP interacts with AKT and TSC2, and knockout of CBAP or serum starvation leads to an increase in TSC1 in the Akt/TSC2 immunoprecipitation complexes. Lysosomal-anchored CBAP was found to override serum starvation and promote S6K1 and 4EBP1 phosphorylation and c-Myc expression in a TSC2-dependent manner. Additionally, recombinant CBAP inhibited the GAP activity of TSC2 complexes in vitro, leading to increased Rheb-GTP loading, likely due to the competition between TSC1 and CBAP for binding to the HBD domain of TSC2. Overexpression of the N26 region of CBAP, which is crucial for binding to TSC2, resulted in a decrease in mTORC1 signaling and an increase in TSC1 association with the TSC2/AKT complex, ultimately leading to increased GAP activity toward Rheb and impaired cell proliferation. Thus, we propose that CBAP can modulate the stability of TSC1-TSC2 as well as promote the translocation of TSC1/TSC2 complexes away from lysosomes to regulate Rheb-mTORC1 signaling.
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http://dx.doi.org/10.1016/j.jbc.2023.105455 | DOI Listing |
J Biol Chem
December 2023
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address:
The Akt-Rheb-mTORC1 pathway plays a crucial role in regulating cell growth, but the mechanisms underlying the activation of Rheb-mTORC1 by Akt remain unclear. In our previous study, we found that CBAP was highly expressed in human T-ALL cells and primary tumors, and its deficiency led to reduced phosphorylation of TSC2/S6K1 signaling proteins as well as impaired cell proliferation and leukemogenicity. We also demonstrated that CBAP was required for Akt-mediated TSC2 phosphorylation in vitro.
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November 2023
Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong 518055, China; International Association for Diagnosis and Treatment of Cancer, Shenzhen, Guangdong 518055, China. Electronic address:
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August 2022
Centro de Investigaciones Biológicas del Noroeste (CIBNOR), Av. Instituto Politécnico Nacional 195, Col. Playa Palo de Sta. Rita, 23096 La Paz, B.C.S Mexico.
This study uses a stochastic bioeconomic approach to estimate the COVID-19 pandemic economic impact on shrimp farming in Mexico. Seeding-harvesting schedules - March-June, May-August, and August-November - were analyzed using shrimp prices and production costs corresponding to 2017-2019 (pre-pandemic) and 2020 (pandemic). The analyses estimated net revenue varied within 597.
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October 2021
FIBMS(Radiology) MBCHB, Al-Hamdanyia General Hospital Mosul Iraq.
Schuurs-Hoeijmakers syndrome is a very rare disorder with less than 60 cases reported worldwide. This is a case report of a patient with SHMS from Iraq, the first in the area of the Middle East. He had epilepsy during his first days of life and a subsequent neurodevelopmental delay.
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