Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains

Abstract

Epigallocatechin gallate (EGCG) is the principal bioactive ingredient in green tea and has been reported to have many health benefits. EGCG influences multiple signal transduction pathways related to human diseases, including redox, inflammation, cell cycle, and cell adhesion pathways. However, the molecular mechanisms of these varying effects are unclear, limiting further development and utilization of EGCG as a pharmaceutical compound. Here, we examined the effect of EGCG on two representative transmembrane signaling receptors, integrin alpha IIb beta 3 and epidermal growth factor receptor (EGFR). We report that EGCG inhibits talin-induced integrin alpha IIb beta 3 activation, but it activates alpha IIb beta 3 in the absence of talin both in a purified system and in cells. This apparent paradox was explained by the fact that the activation state of alpha IIb beta 3 is tightly regulated by the topology of beta 3 transmembrane domain (TMD); increases or decreases in TMD embedding can activate integrins. Talin increases the embedding of integrin beta 3 TMD, resulting in integrin activation, whereas we observed here that EGCG decreases the embedding, thus opposing talin-induced integrin activation. In the absence of talin, EGCG decreases the TMD embedding, which can also disrupt the integrin alpha-beta TMD interaction, leading to integrin activation. EGCG exhibited similar paradoxical behavior in EGFR signaling. EGCG alters the topology of EGFR TMD and activates the receptor in the absence of EGF, but inhibits EGF-induced EGFR activation. Thus, this widely ingested polyphenol exhibits pleiotropic effects on transmembrane signaling by modifying the topology of TMDs.