The ZIP6/ZIP10 heteromer is essential for the zinc-mediated trigger of mitosis
- Cell Mol Life Sci. 2021 Feb;78(4):1781-1798. doi: 10.1007/s00018-020-03616-6.
- 1. Department of Pathology, Phramongkutklao College of Medicine, 315 Ratchawithi Road, Thung Phayathai, Ratchathewi, Bangkok, 10400, Thailand.
- 2. Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Redwood Building, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK.
- 3. Departments of Biochemistry and Molecular Biology, Kansas City, USA.
- 4. Anatomy and Cell Biology, Medical Center, University of Kansas, Kansas City, KS, 66106, USA.
- 5. School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AT, UK.
- 6. Metal Metabolism Group, Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, 150 Stamford Street, London, SE1 9NH, UK.
- 7. Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Redwood Building, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK. [email protected].
Zinc has been known to be essential for cell division for over 40 years but the molecular pathways involved remain elusive. Cellular zinc import across biological membranes necessitates the help of zinc transporters such as the SLC39A family of ZIP transporters. We have discovered a molecular process that explains why zinc is required for cell division, involving two highly regulated zinc transporters, as a heteromer of ZIP6 and ZIP10, providing the means of cellular zinc entry at a specific time of the cell cycle that initiates a pathway resulting in the onset of Mitosis. Crucially, when the zinc influx across this heteromer is blocked by ZIP6 or ZIP10 specific antibodies, there is no evidence of Mitosis, confirming the requirement for zinc influx as a trigger of Mitosis. The zinc that influxes into cells to trigger Mitosis additionally changes the phosphorylation state of STAT3 converting it from a transcription factor to a protein that complexes with this heteromer and pS38Stathmin, the form allowing microtubule rearrangement as required in Mitosis. This discovery now explains the specific cellular role of ZIP6 and ZIP10 and how they have special importance in the Mitosis process compared to Other ZIP transporter family members. This finding offers new therapeutic opportunities for inhibition of cell division in the many proliferative diseases that exist, such as Cancer.