| Autor: |
Pui-Kei, Wu, Seung-Keun, Hong, Wenjing, Chen, Andrew E, Becker, Rebekah L, Gundry, Chien-Wei, Lin, Hao, Shao, Jason E, Gestwicki, Jong-In, Park |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
Sci Signal |
| ISSN: |
1937-9145 |
| Popis: |
Mortalin [also known as heat shock protein family A (Hsp70) member 9 (HSPA9) or glucose-regulated protein 75 (GRP75)] is a mitochondrial molecular chaperone that is often upregulated and mislocalized in tumors with abnormal activation of the kinases MEK and ERK. Here, we found that mortalin depletion was lethal selectively to tumor and immortalized normal cells expressing the mutant kinase B-Raf(V600E) or the chimeric protein ΔRaf-1:ER, and that MEK-ERK–sensitive regulation of the peptide-binding domain in mortalin was critical to life/death decisions in these cells. Proteomics screening identified adenine nucleotide translocase 3 (ANT3) as a previously unknown mortalin client and life/death effector. Mechanistically, increased MEK-ERK signaling activity and mortalin function converge in opposition on the regulation of mitochondrial permeability. Specifically, whereas MEK-ERK activity increased mitochondrial permeability by promoting the interaction between ANT3 and the peptidyl-prolyl isomerase cyclophilin D (CypD), mortalin decreased mitochondrial permeability by inhibiting this interaction. As such, mortalin depletion increased mitochondrial permeability in MEK-ERK–deregulated cells, to the level triggering cell death. Moreover, chemical inhibitors of mortalin effectively suppressed the proliferation of B-Raf(V600E) tumor cells in vitro and in vivo, including their B-Raf inhibitor-resistant progenies. This specific relationship between mortalin and deregulated MEK-ERK pathway activity suggest that mortalin has potential as a selective therapeutic target. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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