Figure 6. Schematic summary of our findings. MEFs at early passage secrete certain levels of IGFBP5. Secreted IGFBP5 proteins inhibit MEK/ERK2 by attenuating their phosphorylation (P) in the neighboring cell, leading to suppression of cellular senescence. IGFBP5 secretion is decreased during serial passage, causing activation of ERK2 and cellular senescence.