Bovine sperm acrosome reaction induced by G protein-coupled receptor agonists is mediated by epidermal growth factor receptor transactivation

Abstract

We have previously demonstrated the presence of active epidermal growth factor receptor (EGFR) and its involvement in sperm capacitation and the acrosome reaction; however, the mechanism of EGFR activation was not clear. We show here that the sperm EGFR can be transactivated by angiotensin II or by lysophosphatydic acid, two ligands which activate specific G-protein-coupled receptors (GPCR), or by directly activating protein kinase A using 8Br-cAMP. This transactivation occurs in noncapacitated sperm and is mediated by PKA, SRC and a metalloproteinase. We also show that the EGFR is activated in sperm incubated under in vitro capacitation conditions, without any added ligand, but not in bicarbonate-deficient medium or when PKA is blocked. Despite the fact that EGFR is activated in capacitated sperm, this state is not sufficient to induce the acrosome reaction. We conclude that the EGFR is stimulated during capacitation via PKA activation, while further activation of the EGFR in capacitated sperm is required in order to induce the acrosome reaction. The acrosome reaction can be induced by GPCR via the transactivation of the EGFR by a signaling pathway involving PKA, SRC and metalloproteinase and the EGFR down-stream effectors PI3K, PLC and PKC.

Role and Regulation of Sperm Gelsolin Prior to Fertilization

“…In a recent study, we reported that the epidermal growth factor receptor (EGFR) is partially activated during sperm capacitation by the cAMP/PKA/SRC mechanisms. It was suggested that EGFR is phosphorylated at the SRC-specific site, suggesting that SRC is active during capacitation (21,22). Additionally, EGFR-mediated signaling is known to activate phospholipase C␥ (PLC␥), to hydrolyze PIP 2 (4,5) , and to cause the subsequent release of PIP 2(4,5) -bound proteins.…”

Sperm Epidermal Growth Factor Receptor (EGFR) Mediates α7 Acetylcholine Receptor (AChR) Activation to Promote Fertilization

“…We showed previously that bovine sperm contains EGFR localized to the sperm head and the mid-piece (50,52). It also has been shown that EGFR is involved in the AR and in actin polymerization during sperm capacitation (39,50,52). Moreover, EGFR phosphorylation/ activation is increased during capacitation.…”

“…The activation of the EGFR generates a Ca 2ϩ signal, broadly defined as the transient rise of the intracellular concentration of Ca 2ϩ (51). We showed previously that bovine sperm contains EGFR localized to the sperm head and the mid-piece (50,52). It also has been shown that EGFR is involved in the AR and in actin polymerization during sperm capacitation (39,50,52).…”

“…The active dimers, upon recruitment of adaptor and signaling proteins, initiate multiple signaling events (41)(42)(43)(44)(45). G protein-coupled receptor signaling is mediated by receptor tyrosine kinases such as EGFR in a process called transactivation (46 -49), a mechanism that exists in sperm as well (50). The activation of the EGFR generates a Ca 2ϩ signal, broadly defined as the transient rise of the intracellular concentration of Ca 2ϩ (51).…”

“…Moreover, EGFR phosphorylation/ activation is increased during capacitation. Further stimulation of the EGFR in capacitated sperm reveals increased intracellular calcium levels leading to AR (50).…”