Polymerization of insulin‐like growth factor‐binding protein‐1 (IGFBP‐1) potentiates IGF‐I actions in placenta

Abstract

Insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), the main secretory protein of decidua that binds to IGFs and has been shown to inhibit or stimulate IGFs' bioactivities. Polymerization, one of the posttranslational modifications of IGFBP-1, has been shown to lead to loss of inhibiting effect of IGFBP-1 on IGF-I actions. The current studies were undertaken to elucidate the effects of steroid hormones on IGFBP-1 polymerization in trophoblast cell cultures. Placental tissues were obtained during legal, elective procedures of termination of pregnancy performed between 7 and 10 weeks of gestation, and primary trophoblast cells were separated. IGFBP-1 polymerization was analyzed by SDS-PAGE and immunoblotting. IGFBP-1 was polymerized when IGFBP-1 was added to trophoblast cell cultures. Polymerization of IGFBP-1 was inhibited by the addition of anti-tissue transglutaminase antibody into the culture media. There was an increase in the intensity of polymerized IGFBP-1 bands with the addition of medroxyprogesterone acetate (MPA), while no such difference was observed upon treatment with estradiol. MPA also increased the expression of tissue transglutaminase on trophoblast cell membranes. IGF-I stimulated trophoblast cell migration, while IGFBP-1 inhibited this IGF-I-induced trophoblast response. Addition of MPA attenuated the inhibitory effects of IGFBP-1 on IGF-I-induced trophoblast cell migration. IGFBP-1 was polymerized by tissue transglutaminase on the cell surface of trophoblasts, and MPA increased tissue transglutaminase expression on the cell surface and facilitated IGFBP-1 polymerization. These results suggest that progesterone might facilitate polymerization of decidua-secreted IGFBP-1 and increase IGF-I actions at feto-maternal interface, thereby stimulating trophoblast invasion of maternal uterus.

Transglutaminase 2 has opposing roles in the regulation of cellular functions as well as cell growth and death

“…152, 153, 154 Vitamin A also induces insulin secretion from islets via TG2, 155 and steroid hormone-induced TG2 facilitates the crosslinking of IGFBP1 and increases IGF-I actions. 156 As a controversial effect, inhibitors of TG2, such as monodansylcadaverine and glycine methylester, do not prevent insulin secretion induced by either cAMP or phorbol ester at basal levels (10 nM) of Ca 2+ ; however, these inhibitors prevent insulin secretion induced by Ca 2+ . 157 These data indicate that the transamidation activity of TG2 has a critical role in insulin secretion.…”

Cellular Functions of Tissue Transglutaminase

“…IGFBP-1 was recently found to undergo TG2-mediated polymerization on the surface of trophoblast cells, leading to its deactivation, the disinhibition of IGF, and, ultimately, enhanced IGF-dependent trophoblast cell migration (Shibuya et al, 2011). These findings suggested that progesterone might facilitate TG2-induced polymerization of decidua-secreted IGFBP-1 and increase IGF actions at the feto-maternal interface, thereby stimulating trophoblast invasion of the maternal uterus.…”

Bisphenol A‐induced mechanistic impairment of decidualization

“…Insulin‐like growth factor (IGF)‐binding protein‐1 (IGFBP1) and decidual prolactin (PRL) are known to be biochemical decidualization markers (Brosens et al, 2014; Tamura et al, 2018). IGFBP1 secretion in the endometrium is suggested to be induced by P 4 through the activation of IGFBP1 polymerization (Gao & Tseng, 1997; Shibuya, Sakai, Kabir‐Salmani, Wachi, & Iwashita, 2011). Similarly, the expressions of uterine PRL and PRL receptor correlate positively with P 4 and E 2 levels (do Amaral et al, 2015).…”