The ZIP6/ZIP10 heteromer is essential for the zinc-mediated trigger of mitosis

Abstract

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 pS 38 Stathmin, 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.

SLC39A10 Upregulation Predicts Poor Prognosis, Promotes Proliferation and Migration, and Correlates with Immune Infiltration in Hepatocellular Carcinoma

“… 33 Driven by STAT3, SLC39A10 was also found to interact with SLC39A6 to initiate cell rounding and import zinc into cells to initiate mitosis. 39 In the current study, flow cytometry results demonstrated that SLC39A10 knockdown promoted the apoptosis of HCC cells. Furthermore, the mRNA and protein expression of two important apoptosis inhibitors, BCL-2 and BIRC5/survivin, were proportionally reduced in HCC SLC39A10-knockdown cells.…”

Zinc transporters and their functional integration in mammalian cells

“…ZIP6 and ZIP10 can form respective homodimers targeted to the plasma membrane where they mediate cellular zinc uptake, which often triggers cells to undergo epithelial-to-mesenchymal transition (EMT) ( 86 , 87 , 128 , 129 ), a process by which epithelial cells lose their cell–cell adhesion and gain migratory properties to become multipotent mesenchymal stem cells during embryonic development and tissue regeneration. Interestingly, ZIP6–ZIP10 heterodimers can also trigger mitosis, a process of cell division that requires cell rounding to be initiated ( 130 ). The full differences between these functional heterodimers are still unclear, as contributions of other ZIP transporters, such as ZIP5, have yet to be clarified.…”

“…The essential role of extracellular zinc in cell proliferation was suggested by the ability of zinc to reverse a zinc chelation-induced suppression of cell cycle progression ( 187 ). When the cell was ready to progress into mitosis, ZIP6–ZIP10 heterodimer was upregulated on the plasma membrane to increase zinc influx to specifically activate the normal processes of mitosis such as microtubule reorganization and chromosome condensation ( 130 ). This mechanism was demonstrated in part by the correlation between antibody inhibition of ZIP6 or ZIP10 and the pause of mitotic initiation, even in the presence of mitotic inducers such as nocodazole ( 130 ).…”

Zinc transporter SLC39A13/ZIP13 facilitates the metastasis of human ovarian cancer cells via activating Src/FAK signaling pathway

“…ZIP5 was overexpressed during esophageal tumorigenesis, and played a vital role in esophageal cancer progression [ 25 ]. ZIP10 was involved in the development of breast cancer by forming a heteromer with ZIP6 [ 26 , 27 ]. ZIP14 was identified as a critical mediator of cachexia development in several metastatic cancers, such as metastatic pancreatic, colon, and breast cancers [ 28 , 29 ].…”