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MAP2K6 directly phosphorylates BCL2L13 to mediate mitophagy for suppressing tumorigenicity

Guangsuo Xing1, Yile Huang2, Xiwen Liu3

  • 1Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, State Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.

Cell Reports
|March 26, 2026
PubMed

Insights

Mitogen-activated protein kinase kinase 6/3 (MKK6/MKK3) act as tumor suppressors in lung adenocarcinoma. They promote mitophagy and inhibit tumor growth by phosphorylating BCL2L13, offering a potential therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • The mitogen-activated protein kinase (MAPK) pathway is crucial for cellular processes and implicated in cancer development.
  • The specific roles and subcellular locations of secondary kinases within the MAPK pathway, such as MKK6/MKK3, are not fully understood, particularly in the context of lung adenocarcinoma (LUAD).

Purpose of the Study:

  • To investigate the function and subcellular localization of MKK6/MKK3 in lung adenocarcinoma.
  • To elucidate the molecular mechanism by which MKK6/MKK3 suppress tumor growth, focusing on mitophagy and mitochondrial function.

Main Methods:

  • Identification and characterization of MKK6/MKK3 in LUAD.
  • Analysis of subcellular localization of MKK6/MKK3 in mitochondria and autophagosome interaction sites.
  • Assessment of MKK6 kinase activity and its role in p38-independent pathways.
  • Investigation of MKK6-mediated phosphorylation of BCL2L13 and its impact on mitophagy and oxidative phosphorylation (OXPHOS).

Main Results:

  • MKK6/MKK3 were identified as tumor suppressors that activate mitophagy and inhibit LUAD growth.
  • MKK6/MKK3 exhibit unique subcellular localization at mitochondria and autophagosome interaction sites.
  • MKK6's tumor-suppressive function relies on its kinase activity, independent of p38.
  • MKK6 directly phosphorylates BCL2L13 at Ser426, enhancing BCL2L13-LC3B interaction, promoting mitophagy, and inhibiting OXPHOS, thereby preventing tumor growth.

Conclusions:

  • MKK6/MKK3 function as tumor suppressors in LUAD by promoting mitophagy via direct phosphorylation of BCL2L13.
  • MKK6-mediated BCL2L13 phosphorylation at interorganellar sites impacts mitochondrial quality and tumorigenicity.
  • This pathway represents a potential therapeutic target for lung adenocarcinoma treatment.
Keywords:
CP: cancerCP: metabolismOXPHOSautophagycancer metabolismmetabolismmitochondriamitophagy

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