CARCINOGENESIS AND INITIATION OF CELL CYCLING BY CHARGE-INDUCED MEMBRANE CLUSTERS MAY BE DUE TO MITOGEN RECEPTORS AND NA+/H+ ANTIPORTS

The membrane cluster hypothesis of mitogenesis and carcinogenesis is extended by proposing that much of the Na+ ingress across a cell's plasma membrane at surface charge-induced (SCI) aggregates is due to mitogen-induced activation of Na+/H+ antiports. Intrinsic proteins (including mitogen receptors and antiports) are electrostatically attracted to and become part of the aggregate. In this location, close proximity facilitates antiport activation. Resulting Na+ ingress may cause sustained partial depolarization, cytoplasmic alkalinization, and initiation of cell cycling. Chronic phosphorylation-dephosphorylation at SCI aggregates too weak to induce cycling, may slowly form polyionic bonds between adjacent proteins at the inner lipid layer. These bonds convert the SCI aggregates to 'permanent' clusters that pass to a daughter cell with parental plasma membrane at mitosis, and are associated with malignancy. EGF and PDGF growth factors are used to develop the hypothesis, which is also applied to steroid and dioxin receptors and to oncogene products.