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Health Sciences Center University of Missouri Columbia, Missouri 65212
Address all correspondence and requests for reprints to: James R. Sowers, Health Sciences Center, MA 410, University of Missouri, Columbia, Missouri. E-mail: sowersj{at}health.missouri.edu.
In extrahepatic cells, the low-density lipoprotein (LDL) receptor enhances the uptake of LDL particles by cells that are actively undergoing growth and proliferation (1, 2), processes that increase the need for cholesterol. There is increasing evidence that hormones and growth factors can regulate both LDL receptor levels and cell signaling through these receptors in a variety of nonhepatic cell types (1, 2, 3, 4, 5). In this issue of Endocrinology, Smith et al. (2) report that estrogen increases both LDL receptor gene expression and LDL endocytosis in pituitary somatolactotropic GH3 cells. Furthermore, they demonstrated that estrogen stimulated the expression of a cytoskeletal linker protein, ezrin, and that their physical functional interaction facilitated the endocytosis of LDL.
The observations by Smith et al. (2) corroborate prior observation that estrogen increases cholesterol synthesis and uptake in pituitary lactotrophs to meet increased demand for cholesterol created by estrogen-induced cellular hypertrophy and proliferation (6, 7, 8). However, the current study also increases our understanding of the mechanism involved in LDL receptor endocytosis. The LDL receptor is a nutrient (i.e. cholesterol) conveyer, which is endocytosed and recycled back to the cell membrane (1). There are adaptor and accessory proteins, which interact with the cytoplasmic domain of the LDL receptor and increase the efficiency of LDL receptor endocytosis. One such adaptor protein is ezrin, a scaffolding protein that links membrane proteins to the cortical actin cytoskeleton (9, 10). It had previously been observed that estrogen stimulates ezrin gene expression in the rat pituitary cells (9, 10) and that, like the LDL receptor, ezrin is expressed at elevated levels in proliferation cells (11). Smith et al. (2) observed that LDL particles substantially colocalized with the active form of ezrin and phosphorylated ezrin at the plasma membrane but, after endocytosis into the cytoplasm, they no longer colocalized. Employing a dominant negative form of ezrin, to inhibit the function of endogenous ezrin, they also showed the LDL was markedly decreased.
The mechanism by which ezrin interacts with the LDL receptor is suggested by several observations. For example, the cytoplasmic domain of the LDL receptor contains a binding site for the clathrin-coated pit adaptor protein complex, AP-2 (12), and ezrin interacts with the AP-2 binding site in a cell-adhesion molecule (13). Ezrin may also interact indirectly with the LDL receptor through a scaffolding protein, as the ezrin-interacting PD2 domain has been shown to interact with the LDL receptor (14, 15). Regardless of the precise mechanism, a clearer understanding of this interaction has important implications for dissecting the actions of estrogen to couple the LDL receptor to the endocytic recycling machinery in cells undergoing estrogen-induced hypertrophy and proliferation, such as lactotrophic reproductive and malignant cells.
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Received March 29, 2004.
Accepted for publication April 1, 2004.
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| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
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