Fig. 2
Molecular mechanisms by which GPER stimulates EVT migration/invasion through the Hippo pathway. When GPER is activated by E2 or G-1, its Gαq subunit stimulates Rho GTPase, which in turn causes actin cytoskeleton organization, a crucial regulator of the Hippo pathway. Actin cytoskeleton inhibits LATS1/2 activity, thus increasing the translocation of YAP protein to the nucleus. Disruption of actin cytoskeleton or inhibition of Rho GTPase facilitate the phosphorylation/activation of LATS1/2 and subsequent inhibition of YAP nuclear translocation and activity. This results in cytoplasmic retention of YAP and its proteolytic degradation. However, the inhibition of LATS1/2 by the actin cytoskeleton is a crucial mechanism responsible by YAP transcriptional activity in the nucleus, where this protein encodes the synthesis of ANGPTL4. When ANGPTL4 is produced, it modulates the EVT cell migration/invasion and subsequent spiral artery remodeling. Additional mechanisms involved in the GPER-induced ANGPTL4 synthesis by the Hippo pathway are provided in this figure and have been published elsewhere [142]. GPER, G protein-coupled estrogen receptor; EVT, extravillous trophoblast; Hippo pathway, Hippo tumor-suppressor pathway; LATS1/2, large tumor suppressor 1 and 2 kinases; YAP, Yes-associated protein; ANGPTL4, angiopoietin-like 4. This artwork was created using the BioRender software