PI3K/Akt And ERK1/2 signalling pathways are involved in endometrial cell migration induced by 17β-estradiol and growth factors

Abstract

Cell motility and invasion are crucial events for endometrial cells, not only for the establishment of pathological states but also during the physiological tissue remodelling that occurs during the menstrual cycle and embryo implantation. We have characterized these phenomena in endometrial stromal cells evaluating cell migration-specific stimuli and the biochemical pathways involved. Ability of endometrial cells to migrate on collagen type IV substrate was evaluated by means of chemotaxis experiments. Modulation of this phenomenon by different growth factors and steroid hormones and their ability to activate extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3 kinase (PI3K)/Akt signalling in this context were examined. Platelet-derived growth factor (PDGF)-BB, epidermal growth factor and fibroblast growth factor-2 as chemoattractant agents stimulated basal migration of endometrial stromal cells through the rapid activation of both ERK1/2 and PI3K/Akt signalling pathways. Experiments using wortmannin and PD98059, specific inhibitors of the PI3K/Akt and ERK1/2 activity, respectively, showed that the activation of both pathways is required for growth-factor-induced cell motility responses. Similarly, 17beta-estradiol (10(-6)-10(-8) M) could enhance both constitutive and PDGF-induced migration of the cells and their rapid treatment with the hormone significantly increased phosphorylation of ERK1/2 and Akt. Conversely, progesterone did not interfere with the basal migration but inhibits the PDGF-induced motility of this cell type. Rapid activation of intracellular signalling cascades ERK1/2 and PI3K/Akt by growth factors and estrogens is involved in the migration of normal endometrial stromal cells.

Expression, activation, and role of AKT isoforms in the uterus

“…In contrast to these observations, death effector domain-containing protein (Dedd) K/K mice implantation sites exhibited decreased AKT protein levels, accompanied by a structural disintegration of the sites and implantation failures; forced expression of AKT1 partially restored polyploidy of the decidual cells, an important marker of successful decidualization, and thus, receptive endometrium (Mori et al 2011). AKT has also been shown to regulate endometrial cell migration in response to chemoattractants (PDGF-BB, EGF, and FGF2) as well as 17b-estradiol (E 2 ), further cementing AKT role in the dynamic process of decidualization (Gentilini et al 2007). In farm animals, a very recent report has shown that IGF1 provided a crucial stimulatory signal in primary porcine trophectoderm cells (pTr), through the PI3K/Akt pathway.…”

Estrogen-dependent expression and subcellular localization of the tight junction protein claudin-4 in HEC-1A endometrial cancer cells

“…The effects of estradiol (E 2 ) on reproductive tract structure and function are well known. Recently, however, studies have indicated a role for E 2 in tumor initiation and progression through its promotion of the proliferative, migratory and invasive capabilities of cells (2)(3)(4)(5)(6). Many of the changes that occur in the endometrium during tumorigenesis are similar to those observed during implantation.…”

The role of MTOR in mouse uterus during embryo implantation

“…Embryo implantation is a complex physiological process and depends on a series of key events, including blastocyst migration, apposition and adhesion to the luminal epithelium, extensive degradation and remodeling of extracellular matrix, invasion of the maternal endometrium by the trophoblast cells of the developing blastocyst, and secretion of embryonic factors, which elicit a cellular reaction in the maternal endometrium (Carson et al 2000, Achache & Revel 2006, Gentilini et al 2007. Numerous signaling proteins such as ERKs, phosphatidylinositol 3-kinase (PI3K), RHO/ROCK, PTK2, or PI3K/AKT/mammalian target of rapamycin (MTOR) are involved in the process to coordinate and integrate these events so as to guarantee successful implantation (Pollheimer & Knofler 2005, Gentilini et al 2007.…”

“…Numerous signaling proteins such as ERKs, phosphatidylinositol 3-kinase (PI3K), RHO/ROCK, PTK2, or PI3K/AKT/mammalian target of rapamycin (MTOR) are involved in the process to coordinate and integrate these events so as to guarantee successful implantation (Pollheimer & Knofler 2005, Gentilini et al 2007.…”