Inhibition of Zinc Transporter ZIP6/ZIP10 Heteromer Prevents the Zinc Influx Required to Trigger Mitosis

Zinc has been known to be essential for cell division for over 40 years, but the exact mechanism remains elusive. Cellular zinc import necessitates the help of the SLC39A family of ZIP transporters, two of which are known to be essential for gastrulation, which involves cell rounding and detachment. We have discovered a new molecular process that explains why zinc is required for cell division, involving these two zinc channels ZIP6 (previously LIV-1) and ZIP10 as a heteromer, providing cellular zinc entry to initiate the onset of mitosis. Crucially, blocking this ZIP6/ZIP10 heteromer-mediated zinc influx by specific antibodies completely prevents mitosis, even in the presence of mitosis causing agent nocodazole, confirming the requirement for this zinc influx as a mitosis trigger. This zinc influx additionally changes STAT3 phosphorylation to pS727STAT3, a poorly understood form of STAT3, stopping transcription factor activity and complexing with this heteromer throughout mitosis alongside pS38Stathmin, the form required for mitotic microtubule rearrangement. This discovery clarifies a role for ZIP6, ZIP10 and STAT3 in mitosis in addition to their known role in gastrulation, offering new opportunities for investigating the processes of cell development and cell division.