The mitogen-activated protein kinase (MAPK) pathway widely regulates development and cancer. However, the subcellular localization and function of the secondary kinases in the MAPK pathway remain unclear. Here, we identified mitogen-activated protein kinase kinase 6 or 3 (MKK6/MKK3) as tumor suppressors that could significantly activate mitophagy and suppress tumor growth in lung adenocarcinoma (LUAD). Mechanistically, among MKK1-7, only MKK6/MKK3 exhibited subcellular organellar localization in mitochondria and autophagosome interaction site. The function of MKK6 in mitophagy and tumorigenicity was dependent on its kinase activity, but not through p38. MKK6 directly phosphorylated BCL2L13 at serine 426, enhancing the interaction between BCL2L13 and LC3B, which, in turn, promoted mitophagy, inhibited oxidative phosphorylation (OXPHOS), and prevented tumor growth. Our studies not only revealed that MKK6-BCL2L13 phosphorylation at the interorganellar site can affect mitochondrial quality in tumorigenicity but also might provide a potential therapeutic strategy for LUAD treatment.
Xing et al. (2026) studied this question.