Changes in intracellular pH regulate many cell behaviors, including proliferation, migration, and transformation. However, our understanding of how physiological changes in pH affect protein conformations and macromolecular assemblies is limited. We present design principles, current modeling predictions, and examples of pH sensors or proteins that have activities or ligand-binding affinities that are regulated by changes in intracellular pH. Changes in intracellular pH (pH_i) regulate a number of normal and pathological cell processes. Increases in pH_1 are permissive for growth factor-induced cell proliferation (22, 40, 80), cell cycle progression (82, 106), and differentiation (12, 107, 112) and are necessary for haptokinetic migration (21, 44, 47, 85, 96) and ameboid chemotaxis (78, 86, 94, 108). Additionally, increased cytosolic pH is a hallmark of transformed cells from different tissue origins and genetic backgrounds, making it a common characteristic of distinct cancers (16, 36) and possibly a common critical driving force for tumor progression (81, 85). A decrease in cytosolic pH promotes caspase-dependent and -independent apoptosis (46, 59, 119), and in response to some apoptotic signals precedes mitochondrial dysfunction (52). Because cytosolic pH homeostasis is tightly regulated (11), dramatic differences in cell behavior are driven by relatively small changes in pH_i. The increased pH_i in transformed cells is only 0.3-0.5 pH units greater than in normal cells, which is generally maintained at -7.2, and apoptosis is triggered at 0.3-0.4 pH units lower than normal.
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