Phosphorylated HAND1 contributes to trophoblast cell migration during placentation by activating the Vav2-Rac1-PAK signaling.

Trophoblastic cell migration is essential for the attachment of the placenta to uterine wall, which is a critical step for fetal development. Aberrant migration of trophoblastic cells can lead to pregnant pathologies such as preeclampsia (PE), while the molecular mechanisms remain largely unknown. The current study investigated the effects and molecular mechanisms of the HAND1-Rac1-PAK axis in trophoblast migration using the HTR-8/SVneo cell line, isolated human primary cytotrophoblasts, and human placental tissues. We report herein that HAND1 is highly expressed in human early placenta and promotes trophoblastic cell migration. Mechanistically, HAND1 potentiates human trophoblastic cell migration via activating Vav2/Rac1/PAKs signaling, and the elevated capacity of HAND1 in inducing migration is dependent on its Serine/Threonine phosphorylation status, which is reciprocally regulated by PAK2 and is directly associated with the subsequent degradation of HAND1 protein, thereby generating a positive feed-back for HAND1-mediated trophoblasts migration during human pregnancy. The data suggest that HAND1 is essential for regulating human trophoblast function, potentially enhancing our understanding of pregnancy maintenance and contributing to new therapies for gestational disorders.