Zinc transporter 2 interacts with vacuolar ATPase and is required for polarization, vesicle acidification, and secretion in mammary epithelial cells.
An important feature of the mammary gland is its ability to undergo profound morphological, physiological, and intracellular changes to establish and maintain secretory function. During this process, key polarity proteins and receptors are recruited to the surface of mammary epithelial cells (MECs), and the vesicle transport system develops and matures. However, the intracellular mechanisms responsible for the development of secretory function in these cells are unclear. The vesicular zinc (Zn2+) transporter ZnT2 is critical for appropriate mammary gland architecture, and ZnT2 deletion is associated with cytoplasmic Zn2+ accumulation, loss of secretory function and lactation failure. The underlying mechanisms are important to understand as numerous mutations and non-synonymous genetic variation in ZnT2 have been detected in women that result in severe Zn2+ deficiency in exclusively breastfed infants. Here we found that ZnT2 deletion in lactating mice and cultured MECs resulted in Zn2+-mediated degradation of phosphatase and tensin homolog (PTEN), which impaired intercellular junction formation, prolactin receptor trafficking, and alveolar lumen development. Moreover, ZnT2 directly interacted with vacuolar H+-ATPase (V-ATPase), and ZnT2 deletion impaired vesicle biogenesis, acidification, trafficking, and secretion. In summary, our findings indicate that ZnT2 and V-ATPase interact and that this interaction critically mediates polarity establishment, alveolar development, and secretory function in the lactating mammary gland. Our observations implicate disruption in ZnT2 function as a modifier of secretory capacity and lactation performance.
['Lee|Sooyeon|S|', 'Rivera|Olivia C|OC|', 'Kelleher|Shannon L|SL|']
D000818:Animals D001692:Biological Transport D002352:Carrier Proteins D027682:Cation Transport Proteins D016764:Cell Polarity D002478:Cells, Cultured D004847:Epithelial Cells D005260:Female D006706:Homeostasis D007774:Lactation D008321:Mammary Glands, Animal D051379:Mice D018345:Mice, Knockout D051059:PTEN Phosphohydrolase D055571:Secretory Pathway D025262:Vacuolar Proton-Translocating ATPases D015032:Zinc
zinc zinc transporter vacuolar ATPase vesicles acidification secretion mammary gland lactation cell polarity