Integrin beta8 (ITGB8) activates VAV-RAC1 signaling via FAK in the acquisition of endometrial epithelial cell receptivity for blastocyst implantation

Vijay Kumar,Rajesh Kumar Jha,Upendra Kumar Soni,Vineet Kumar Maurya,Kiran Singh

doi:10.1038/s41598-017-01764-7

Vijay Kumar, Rajesh Kumar Jha + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-01764-7

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Abstract

Integrin beta8 (ITGB8) is involved in the endometrial receptivity. The blastocyst first interacts with the luminal endometrial epithelial cells during its implantation; therefore, we have investigated the signaling of ITGB8 via FAK and VAV-RAC1 in the endometrial epithelial cells. Integrin beta8 was found elevated in epithelial cells at late-pre-receptive (day4, 1600 h) and receptive (day5, 0500 h) stages of endometrial receptivity period in the mouse. Integrins downstream molecule FAK has demonstrated an increased expression and phosphorylation (Y397) in the endometrium as well as in the isolated endometrial epithelial cells during receptive and post-receptive stages. Integrin beta8 can functionally interact with FAK, VAV and RAC1 as the levels of phosphorylated-FAK, and VAV along with the RAC-GTP form was reduced after ITGB8 knockdown in the endometrial epithelial cells and uterus. Further, VAV and RAC1 were seen poorly active in the absence of FAK activity, suggesting a crosstalk of ITGB8 and FAK for VAV and RAC1 activation in the endometrial epithelial cells. Silencing of ITGB8 expression and inhibition of FAK activity in the Ishikawa cells rendered poor attachment of JAr spheroids. In conclusion, ITGB8 activates VAV-RAC1 signaling axis via FAK to facilitate the endometrial epithelial cell receptivity for the attachment of blastocyst.

Highlights

Endometrial receptivity is a predefined and restricted period known as the ‘window of endometrial receptivity’ which is crucial to facilitate the blastocyst implantation and induces various mechanisms originating from the blastocyst and endometrium
Integrin beta[8] is upregulated during the receptive stage in the uterine epithelial cells during window of endometrial receptivity period in a mouse model and directs its downstream signaling through Focal Adhesion Kinase (FAK)
Integrin beta8 (ITGB8) in the endometrium and it was predominant in the luminal epithelial cells, which is essential for embryo implantation process[10]

Summary

Introduction

Endometrial receptivity is a predefined and restricted period known as the ‘window of endometrial receptivity’ which is crucial to facilitate the blastocyst implantation and induces various mechanisms originating from the blastocyst and endometrium. Integrins can serve as extracellular matrix (ECM) receptor, it can trigger downstream molecules like focal adhesion kinase (FAK) and propagate the signaling cascade. FAK is an important modulator of angiogenesis as the study of transgenic mouse models indicated that both the expression and activity of FAK are essential in the endothelial cells for the formation of new blood vessel network during embryonic development[13,14,15] It is well studied key component of the signal transduction pathway, which is triggered/activated by the integrins. FAK is distributed differentially on endometrial cells during the process of embryo attachment[21] and is expressed during decidualization[22] and blastocyst outgrowth predominantly[23] It acts as a potential biochemical determinant of trophoblast invasion[24]. Apart from the adhesion process of integrin during the lodging process of a blastocyst on the endometrial cells to facilitate the implantation process, they may trigger the intracellular signaling pathways via various biochemical messengers, but this needs further investigation, which is being reported in the present study

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