iProXProteomicsXingguo LiuHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0015869000liu_xingguo@gibh.ac.cnGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesiProXThe 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.MAP2K6 directly phosphorylates BCL2L13 to mediate mitophagy for suppressing tumorigenicity.Xing Guangsuo G, Huang Yile Y, Liu Xiwen X, Li Linpeng L, Liu Zichao Z, Wu Yi Y, Zhou Yanshuang Y, Ding Yingzhe Y, Chen Baodan B, Xue Guanru G, Li Zijing Z, Hao Zhihong Z, Liu Yang Y, Fan Wenhui W, Ding Haolin H, Liang Shan S, He Jingcai J, Wang Junwei J, Zhang Jian J, Qin Dajiang D, Wang Wuming W, Lu Gang G, Chan Wai-Yee WY, Ran Pixin P, Ju Huaiqiang H, Dong Ming M, Liang Wenhua W, Liu Xingguo X, Chen Keshi KfalseMAP2K6 Directly Phosphorylates BCL2L13 to Mediate Mitophagy for Suppressing TumorigenicityRaw MS data of proteomic or phosphoproteomic in A549 cellsThu Feb 26 00:00:00 GMT 2026PXD074976960641886451