A potential function of RLIP76 in the ovarian corpus luteum

Abstract

Ral interacting protein of 76 kDa (RLIP76) is multifunctional protein localized and distributed in the plasma membrane, cytosol, and nucleus of the cell. In tumorigenesis, RLIP76 emerges as a common feature for the solid tumor growth. RLIP76 is ubiquitously expressed in various tissues including the ovary. Interestingly, the similar physiological events in obtaining an adequate supply of nutrient by gaining access to the host vascular system are required either for corpus luteum formation or tumor development. In addition, the identical angiogenesis modulators were found in neoplastic and normal ovaries. Our previous study involving RLIP76-/- mice implanted with melanoma or carcinoma cell conclusively demonstrated that RLIP76 is necessary for angiogenesis and neovascularization of primary solid tumors. RLIP76 plays an essential role in tumor angiogenesis through the regulation of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1). In certain previous studies, those pro-angiogenic factors were found significantly to be upregulated during the corpus luteum formation. To that, the following review will discuss the likelihood of RLIP76 role in ovarian corpus luteum.

Keywords: Angiogenesis; Corpus luteum; Ovary; RLIP76.

Fig. 1

Multiple functions of RLIP76. RLIP76 is a modular protein harboring an N-terminal region, a Rho-Gap region, a Ral binding region, and a C-terminal region. RLIP76 is capable of interacting with diverse functional proteins through its variety of domains and motifs. Thus, RLIP76 is a multifunctional protein involved in various cellular and physiological functions such as endocytosis, metabolite transport, stress responses, mitosis, actin remodeling, cell migration and spreading

Fig. 2

The proposed schematic diagram of RLIP76 role in angiogenesis. In response to pro-angiogenic factors stimulation, RLIP76 mainly participates in mediating the activation of PI3K/Akt signaling pathway that induces further activation of HIF-1. The activation of HIF-1 is required for promoting the VEGF expression that is essential for angiogenesis and cell migration and spreading. In addition, RLIP76 actively participates in regulating Rac1 and Arf6 signaling pathway that heavily contributes to cell spreading and migration. Thus, RLIP76 plays an important role as a critical link in a small GTPases downstream effect in response to membrane transduction of pro-angiogenic factors in which is vital for tumor angiogenesis

Fig. 3

RLIP76 potential function in ovarian corpus luteum. The tumor and corpus luteum share similar physiological events in obtaining an adequate supply of nutrient by gaining access to the host vascular system. In tumor development, RLIP76 actively participates in regulating the cell migration and spreading required for angiogenesis. Furthermore, RLIP76 plays an essential role in tumor angiogenesis through the regulation of pro-angiogenic factors such as VEGF and HIF-1. In addition, those pro-angiogenic factors were discovered to be upregulated during the corpus luteum angiogenesis. Taken together, the RLIP76 may be required for corpus luteum formation and its physiological function. However, further investigation is necessary to discover and elucidate the potential function of RLIP76 in ovarian corpus luteum regulation