Phosphorylation of INF2 by AMPK promotes mitochondrial fission and oncogenic function in endometrial cancer

Ding, Yan; Lv, Zeheng; Cao, Wenxin; Shi, Wenming; He, Qizhi; Gao, Kun

doi:10.1038/s41419-024-06431-0

Cited by 5 publications

(1 citation statement)

References 38 publications

(54 reference statements)

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“…INF2 protein in the ER can trigger mitochondrial division by recruiting DRP1 protein, and elevated INF2 has been significantly, negatively correlated with the hypocancerous FBXO7 protein in endometrial cancer specimens ( 98 ). Under energetic stress conditions, AMPK induces phosphorylation of INF2 (Ser1077), leading to its increased localization to the ER, which enhances DRP recruitment to mitochondria and promotes endometrial cancer cell growth ( 99 ).…”

Section: Cellular Organelle Mechanisms In Endometrial Cancer Pathogen...mentioning

confidence: 99%

Independent organelle and organelle—organelle interactions: essential mechanisms for malignant gynecological cancer cell survival

Shen,

Chen,

et al. 2024

Front. Immunol.

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Different eukaryotic cell organelles (e.g., mitochondria, endoplasmic reticulum, lysosome) are involved in various cancer processes, by dominating specific cellular activities. Organelles cooperate, such as through contact points, in complex biological activities that help the cell regulate energy metabolism, signal transduction, and membrane dynamics, which influence survival process. Herein, we review the current studies of mechanisms by which mitochondria, endoplasmic reticulum, and lysosome are related to the three major malignant gynecological cancers, and their possible therapeutic interventions and drug targets. We also discuss the similarities and differences of independent organelle and organelle–organelle interactions, and their applications to the respective gynecological cancers; mitochondrial dynamics and energy metabolism, endoplasmic reticulum dysfunction, lysosomal regulation and autophagy, organelle interactions, and organelle regulatory mechanisms of cell death play crucial roles in cancer tumorigenesis, progression, and response to therapy. Finally, we discuss the value of organelle research, its current problems, and its future directions.

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Section: Cellular Organelle Mechanisms In Endometrial Cancer Pathogen...mentioning

confidence: 99%

Independent organelle and organelle—organelle interactions: essential mechanisms for malignant gynecological cancer cell survival

Shen,

Chen,

et al. 2024

Front. Immunol.

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AMPK: The energy sensor at the crossroads of aging and cancer

Penugurti,

Manne,

Bai

et al. 2024

Seminars in Cancer Biology

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Missense Mutant Gain-of-Function Causes Inverted Formin 2 (INF2)-Related Focal Segmental Glomerulosclerosis (FSGS)

Subramanian,

Williams,

Karp

et al. 2024

Preprint

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Inverted formin-2 (INF2) gene mutations are among the most common causes of genetic focal segmental glomerulosclerosis (FSGS) with or without Charcot-Marie-Tooth (CMT) disease. Recent studies suggest that INF2, through its effects on actin and microtubule arrangement, can regulate processes including vesicle trafficking, cell adhesion, mitochondrial calcium uptake, mitochondrial fission, and T-cell polarization. Despite roles for INF2 in multiple cellular processes, neither the human pathogenic R218Q INF2 point mutation nor the INF2 knock-out allele is sufficient to cause disease in mice. This discrepancy challenges our efforts to explain the disease mechanism, as the link between INF2-related processes, podocyte structure, disease inheritance pattern, and their clinical presentation remains enigmatic. Here, we compared the kidney responses to puromycin aminonucleoside (PAN) induced injury between R218Q INF2 point mutant knock-in and INF2 knock-out mouse models and show that R218Q INF2 mice are susceptible to developing proteinuria and FSGS. This contrasts with INF2 knock-out mice, which show only a minimal kidney phenotype. Co-localization and co-immunoprecipitation analysis of wild-type and mutant INF2 coupled with measurements of cellular actin content revealed that the R218Q INF2 point mutation confers a gain-of-function effect by altering the actin cytoskeleton, facilitated in part by alterations in INF2 localization. Differential analysis of RNA expression in PAN-stressed heterozygous R218Q INF2 point-mutant and heterozygous INF2 knock-out mouse glomeruli showed that the adhesion and mitochondria-related pathways were significantly enriched in the disease condition. Mouse podocytes with R218Q INF2, and an INF2-mutant human patient’s kidney organoid-derived podocytes with an S186P INF2 mutation, recapitulate the defective adhesion and mitochondria phenotypes. These results link INF2-regulated cellular processes to the onset and progression of glomerular disease. Thus, our data demonstrate that gain-of-function mechanisms drive INF2-related FSGS and explain the autosomal dominant inheritance pattern of this disease.

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Phosphorylation of INF2 by AMPK promotes mitochondrial fission and oncogenic function in endometrial cancer

Cited by 5 publications

References 38 publications

Independent organelle and organelle—organelle interactions: essential mechanisms for malignant gynecological cancer cell survival

Independent organelle and organelle—organelle interactions: essential mechanisms for malignant gynecological cancer cell survival

AMPK: The energy sensor at the crossroads of aging and cancer

Missense Mutant Gain-of-Function Causes Inverted Formin 2 (INF2)-Related Focal Segmental Glomerulosclerosis (FSGS)

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