The Fer Tyrosine Kinase Mediates EGFR Activation in Sperm Capacitation

Mammalian sperm cells must undergo several processes collectively called capacitation before carrying out the acrosome reaction (AR), which is required for sperm penetration into the oocyte. The spontaneous acrosomal reaction (SAR), which can occur before the sperm cell reaches the vicinity of the oocyte, impairs the fertilizing ability of the sperm. This study examined the role of the Fer tyrosine kinase in sperm fertilizing activity. Inhibition of the Fer activity led to a 75% reduction in IVF rates in mice, indicating a critical role for Fer in fertilization. Further investigation of Fer's role during sperm capacitation focused on its potential interaction with the epidermal growth factor receptor (EGFR). Inhibition of Fer during capacitation significantly decreased the EGFR activation state and increased the incidence of SAR, whereas inhibition of Fer during the acrosome reaction step had no effect on the EGF-induced AR. The effects of Fer inhibition on EGFR activation and SAR enhancement are mediated by the Ca²⁺ channel, CatSper. Notably, reduction in Ca²⁺ influx by CatSper inhibition revealed a significant increase in Fer phosphorylation/activation, while increasing intracellular Ca²⁺ concentrations completely inhibited this effect. Additionally, we show that Fer activation depends on a signaling cascade involving protein kinase A (PKA) that leads to EGFR activation through the following pathway: HCO₃^- → SAC → cAMP → PKA → Src → Fer → EGFR. Collectively, we decipher in this work a new regulatory cascade that leads to the Fer-directed activation of EGFR in sperm capacitation.