Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 4, Pages 1475-1491Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI65703
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Funding
- NIH [R01 DK-079798-01, R01 DK58587, R01 CA 77955, P01 116037]
- American Cancer Society [DDC-115769]
- DDRCC [P30 DK052574]
- Texas Medical Center Digestive Diseases Center [DK56338]
- Italian Association for Cancer research (AIRC)
- Vanderbilt Digestive Disease Research Center [P30 DK 508404]
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After cell fate specification, differentiating cells must amplify the specific subcellular features required for their specialized function. How cells regulate such subcellular scaling is a fundamental unanswered question. Here, we show that the E3 ubiquitin ligase Mindbomb 1 (MIB1) is required for the apical secretory apparatus established by gastric zymogenic cells as they differentiate from their progenitors. When Mib1 was deleted, death-associated protein kinase-1 (DAPK1) was rerouted to the cell base, microtubule-associated protein 1B (MAP1B) was dephosphorylated, and the apical vesicles that normally support mature secretory granules were dispersed. Consequently, secretory granules did not mature. The transcription factor MIST1 bound the first intron of Mib1 and regulated its expression. We further showed that loss of MIB1 and dismantling of the apical secretory apparatus was the earliest quantifiable aberration in zymogenic cells undergoing transition to a precancerous metaplastic state in mouse and human stomach. Our results reveal a mechanistic pathway by which cells can scale up a specific, specialized subcellular compartment to alter function during differentiation and scale it down during disease.
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