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Liang and colleagues reveal the architecture of the human KICSTOR complex and show that C12orf66 anchors it to the lysosomal membrane via a cationic patch and protruding loop. This positioning enables...

【Life Sci】AIMS: Major depressive disorder (MDD) represents a major contributor to disability, yet currently prescribed monoamine-b

ESR1-mutant breast cancers show increased mutational burden, proliferation, and enhanced mTORC1 signaling, linking ER activity to tumor aggressiveness. A multi-omic signature predicts ESR1 mutations and identifies patients at higher risk of recurrence and poor outcomes.

Loss-of-function mutations in the GATOR1 complex (NPRL2, NPRL3, and DEPDC5) are among the most common genetic causes of epilepsy. These mutations impair amino acid-dependent regulation of mTORC1 and c...

Read the full paper: Repressed mTORC1 signaling and transient dendritic pruning support axonal regeneration in adult zebrafish

Loss of the tumor suppressor PTEN is common in T-cell acute lymphoblastic leukemia (T-ALL) and is associated with poor prognosis. PTEN-loss drives AKT/mTORC1 signaling to promote leukemic cell growth....

Peripheral neuropathy affects over 18 million adults in the United States ( [Hicks et al., 2021][1]), but therapeutic outcomes are poor due to a lack of regenerative treatments. Development of novel, disease-modifying therapies is hindered by poor understanding of the mechanisms promoting axonal regeneration in peripheral neurons. Pten is a strong negative regulator of cell growth, and Pten-KO drives axonal regeneration in various neuronal subtypes potentially via downstream regulation of stability of the microtubule (MT) cytoskeleton, a vital component of axonal growth. While Pten-KO accelerates MT polymerization rates in the axonal growth cone, it remains unknown whether this action is dependent on mTORC1 or mTORC2 signaling and regeneration under Pten-KO is dependent on MT activation. Here, we perform in vitro codeletions of either Raptor (mTORC1) or Rictor (mTORC2) alongside Pten-KO in mouse peripheral sensory neuron cultures of either sex to isolate the effects of each pathway on the MT cytoskeleton. We use Pten-KO to increase MT polymerization and neuronal outgrowth and then show that suppression of mTORC2, but not mTORC1, is sufficient to reduce the accelerated MT polymerization and neuronal hypertrophy to wild-type levels. These results are specific to the axonal growth cone, and MT dynamics in the proximal axon shaft are not impacted by Pten-KO, mTORC1 suppression, or mTORC2 suppression. Our results help elucidate the mechanism by which Pten regulates the MT cytoskeleton and axonal outgrowth in peripheral sensory neurons, localize where this occurs in the axon, and highlight the MT cytoskeleton as a potential molecular target for regenerative therapies. [1]: #ref-18

ESR1-mutant breast cancers show increased mutational burden, proliferation, and enhanced mTORC1 signaling, linking ER activity to tumor aggressiveness. A multi-omic signature predicts ESR1 mutations a...

New research in adult zebrafish shows that transient dendritic pruning driven by repressed mTORC1 signaling is essential for efficient axonal regeneration, challenging growth-promotion strategies in

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Read the full paper: Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired

Read the full paper: EZH2-dependent phenotypic plasticity reveals TTP-associated and mTORC1 therapeutic vulnerabilities in lethal prostate cancer

Proteomic and phosphoproteomic analyses of lysosomes identify a nutrient-independent regulatory arm of mTORC1 signalling that mediates lysosomal adaptation to stress and whose deregulation underlies tumorigenesis in follicular lymphoma.

German et al. use integrated multi-omics analysis to identify EZH2 as a central regulator of prostate cancer phenotypic plasticity. The study reveals TTP-associated pathways and adaptive PI3K/mTORC1 as mediators of response to EZH2 inhibition and demonstrates that co-targeting EZH2 and PI3K/mTORC1 is an effective strategy in aggressive prostate cancer models.

Akt is required for intestinal integrity, and Akt1/Akt2 intestinal deletion induces rapid mortality in mice, which is recapitulated by pan-PI3K and Akt inhibitors, and is reversed by activating mTORC1 via additional deletion of either FoxO1 or Tsc1.