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The mTOR Family of Proteins and the Regulation of Trophoblast Invasion by Gas6

Kelsey M Hirschi, Kary Ya Fang Tsai, Miki M Edwards, Parker Hall, Juan F Mejia, Camilo A Mejia, Paul R Reynolds and Juan A Arroyo*

Objective: Preeclampsia is an obstetric complication wherein trophoblast invasion is decreased and high levels of serum Gas6 protein are present. Our objective was to assess members of the mTOR family that are plausibly involved in the invasion of trophoblast cells resulting from Gas6/AXL activation.

Methods: Human first trimester cell line; (SW71), placental choriocarcinoma cell line (Jeg-3) and pulmonary alveolar type II-like cell line (A549) were treated with Gas6 or Gas6 and R428 (AXL receptor inhibitor) for 24 hours and real time cellular invasion was determined. Western blots were utilized to assess AXL receptor expression in treated and control cells. An Akt/mTOR phospho protein multiplex approach was used to determine the activity of mTOR related proteins.

Results: As compared to controls, cell treatments showed: 1) decreased SW71 invasion and increased Jeg-3 and A549 invasion with Gas6, 2) reversal of invasive properties when Gas6 and R428 were co-administered in A549 and SW71 cells, 3) increased expression of pAXL cells with Gas6, 4) decreased pAXL expression when Gas6 and R428 were added, 5) a trend of decreased phosphorylation of mTOR related proteins by Gas6 in trophoblasts, and 6) a trend of increased phosphorylation of mTOR related proteins by Gas6 in lung cancer cells.

Conclusions: These experiments revealed that mTOR family members are involved in the activation of AXL receptors during the regulation of cell invasion. The results provide important insight into the mechanism of AXL regulation of trophoblast cell invasion and identify potential avenues that may help in the understanding of obstetric complications associated with the aberrant invasion of trophoblast cells.