Endocrine Abstracts

Even though serine-threonine kinase PAK1 is activated by estrogen and plays an important role in breast cancer, the role of PAK1 in estrogen response is not fully understood. We have shown that estrogen activates PAK1 through both ERα and GPER1 plasma membrane receptors and that cytoplasmic Etk/Bmx directly phosphorylates Tyr153-PAK1 and activates PAK1 in response to estrogen. We have described a signaling complex composed of pTyr-PAK1, Etk, the heterotrimeric G-protein subunits, Gβ1, Gγ2 and/or Gγ5, βPIX (PAK-associated guanine nucleotide exchange factor) and PKA (protein kinase A) which, upon formation, activates PAK1 through positive feed-back manner. The PKA catalytic subunit (PKA-Cα) directly phosphorylates PAK1 while the PKA RIIβ subunit is a direct target of PAK1. In response to estrogen, activated pTyr-PAK1 complex reciprocally potentiates PKA activation. PKA phosphorylates Ser305-ERα in response to estrogen. However, in response to prolactin (PRL), Ser305-ERα is phosphorylated by pTyr-PAK1. Our data suggest that in cells exposed to both PRL and estrogen, Ser305-ERα is phosphorylated by both PKA and pTyr-PAK1 resulting in maximal signal. Furthermore, S305-ERα activation leads to enhanced phosphorylation of Ser118-ERα, and promotes cell proliferation and tumor growth. Together, our data strongly support a critical interplay between PRL and estrogen via PAK1. Ligand-independent activation of ERα suggests that PRL/PAK1 may contribute to resistance to anti-estrogen therapies. Thus, we propose that PAK1 serves as a common node for estrogen- and PRL-dependent pathways, making it an attractive target for anti-cancer therapy.