Fig. 5. Proposed mechanism for cytotrophoblast survival at 2% O₂. Activated metalloproteinases (MP) at the cell surface cleave the extracellular domain of proHBEGF (1). The released sHBEGF binds to HER1 or HER4 through its EGF-like domain and to heparan sulfate proteoglycans (HSPG) through its heparin-binding domain (2), and this is followed by receptor homo- or heterodimerization with other members of the HER family. Subsequent transphosphorylation of HER cytoplasmic domains at key tyrosine residues (Y-P) initiates downstream signaling that increases proHBEGF accumulation (3) and inhibits apoptosis (4). This positive feedback loop upregulates HBEGF secretion to achieve extracellular HBEGF levels sufficient to maintain cell survival at 2% O₂.