Oncogenic ERK signaling represses chaperone-mediated autophagy through transcriptional control of LAMP-2A
Berenger, E.; Kacal, M.; Maestri, A.; Kochetkova, E.; Zhang, B.; Sajwan, S.; Mannervik, M.; Norberg, E.; Kaminskyy, V. O.; Vakifahmetoglu Norberg, H.
Show abstract
Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway governed by the rate-limiting receptor LAMP-2A and increasingly implicated in cancer. However, the oncogenic circuits that enforce CMA repression and whether this state is therapeutically reversible remain unclear. Here, we developed a quantitative bioluminescence-based reporter to measure CMA activity in human cancer cells and combined parallel chemical and genome-scale CRISPR-Cas9 screens to define regulatory pathways. The chemical screen identified GSK1059615 as a CMA-restoring compound that increased LAMP-2A transcription and protein abundance in vitro and in vivo. In parallel, the CRISPR screen revealed ERK signaling as a pathway-level suppressor of CMA. Genetic or pharmacologic ERK inhibition de-repressed LAMP-2A expression, while integrated modulation of ERK, PI3K-AKT, and p38 signaling coordinated transcriptional induction and stabilization of LAMP-2A. Transcriptomic analyses further implicated FOXO1/FOXP1-driven programs in LAMP-2A regulation. Together, these findings position CMA as an integrated output of oncogenic signaling networks and establish a mechanistic framework for restoring CMA activity in defined cancer contexts.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells 96%
- A novel non-catalytic scaffolding activity of Hexokinase 2 contributes to EMT and metastasis 96%
- Ca2+-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair 96%
Similar papers in this journal
- Selective MAP1LC3C (LC3C) autophagy requires noncanonical initiation regulators and the paralog-specific C-terminal peptide 96%
- Antigen-derived peptides directly engage the unfolded-protein sensor IRE1α to curb cross-presentation by dendritic cells 95%
- Rapid turnover of CTLA4 is associated with a complex architecture of reversible ubiquitylation. 95%
Similar papers in this journal
- A Cancer-Specific Antigen Drives Histone Acetylation by Stabilizing the Acetyltransferases 96%
- PERK-dependent reciprocal crosstalk between ER and non-centrosomal microtubules coordinates ER architecture and cell shape 96%
- G9a Promotes Breast Cancer Recurrence Through Repression of a Pro-inflammatory Program 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.