The hepatic alpha 2-macroglobulin receptor (alpha 2MR)/low density lipoprotein receptor-related protein (LRP) binds and endocytoses alpha 2-macroglobulin-proteinase complexes in plasma. In addition, it binds lipoproteins, a novel 40 kDa protein, and complexes between plasminogen
activators and plasminogen activator inhibitor type-1.
General function
Receptor
Comment
LRP recognizes at least 30 different ligands that represent several families of proteins. These include
lipoproteins, proteinases, proteinase-inhibitor complexes, ECM proteins, bacterial toxins, viruses, and various
intracellular proteins. By far the largest group of ligands that are recognized by LRP are either proteinases or molecules
associated with regulating proteolytic activity. Certain serine proteinases and metalloproteinases bind directly to LRP,
while a number of other proteinases only bind once complexed with their specific inhibitors. The latter include
members of the Serpin superfamily of serine proteinase inhibitors and the pan-proteinase inhibitors 2M and pregnancy
zone protein. These inhibitors are only recognized by LRP following a conformation change that occurs in them after
proteolytic cleavage or reaction with small amines. In contrast, LRP recognizes both the native and complexed forms of
tissue factor pathway inhibitor (TFPI) (a proteinase inhibitor containing Kunitz-type proteinase inhibitor domains). LRP
also binds to the multimeric matrix proteins thrombospondin-1 and thrombospondin-2 and delivers Pseudomonas
exotoxin A and minor-group human rhinovirus into cells. In addition, LRP recognizes a number of intracellular proteins,
including HSP-96, the HIV-1 Tat protein, and RAP, an endoplasmic reticulum resident protein that functions as a
molecular chaperone for LRP and other LDL receptor family members.
Cellular localization
Plasma membrane
Comment
Ovarian function
Follicle development
Comment
Sisco B, et al 2003 reported the isolation of genes differentially expressed in dominant and subordinate bovine follicles.
In monoovulatory species such as cattle, unknown mechanisms lead to the selection of one of a cohort of developing ovarian follicles to assume dominance and continue to grow in each follicular wave. The authors have used suppressive subtraction hybridization to identify genes differentially expressed in the granulosa cells of dominant and subordinate follicles. Inhibin betaA, apolipoprotein E receptor 2, MAPKkinase kinase 5 (ask1), and carboxypeptidase D were isolated and verified to be reliable markers for dominant follicles using real-time RT-PCR. Before the time point at which dominant follicles can be distinguished by virtue of their deviation in size and growth rate, transcripts for inhibin betaA, apolipoprotein E receptor 2, and p450 aromatase were elevated specifically in the one to three largest follicles. On d 2.5 postovulation, near the time of dominant follicle selection, the mRNA expression profiles of MAPK kinase kinase 5 and carboxypeptidase D paralleled those of the other three genes, thus anticipating the clear molecular expression differences seen between the dominant follicle and the next largest follicle 1 d later.
Expression regulated by
Comment
Ovarian localization
Granulosa
Comment
Moestrup SK, et al reported the distribution of the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues.
Low-density lipoprotein and cAMP cooperate to regulate expression and function of the low-density lipoprotein receptor-related protein in rat ovarian granulosa cells. Azhar S et al. Rat ovarian granulosa rely heavily on lipoprotein-derived cholesterol for steroidogenesis, which is principally supplied by the LDL receptor- and SR-BI-mediated pathways. In the current study, we characterized the hormonal and cholesterol regulation of another member of the LDL receptor superfamily, LRP and its role in granulosa cell steroidogenesis. Co-incubation of cultured granulosa cells with LDL and Bt2cAMP greatly increased the mRNA/protein levels of LRP. Bt2cAMP and Bt2cAMP + hLDL also enhanced SR-BI mRNA levels. However, there was no change in the expression of RAP, a chaperone for LRP, or another lipoprotein receptor, LRP8/apoER2 in response to Bt2cAMP + hLDL, whereas the mRNA expression of LDL receptor was significantly reduced. The induced LRP was fully functional, mediating increased uptake of its ligand, 2-macroglobulin. The level of binding of another LRP ligand, chylomicron remnants, did not increase, although the extent of remnants degradation that could be attributed to the LRP doubled in cells with the elevated levels of LRP. The addition of lipoprotein type LRP ligands such as chylomicron remnants and VLDL to incubation medium significantly increased the progestin production in both under basal and stimulated conditions. In summary, our studies demonstrate a role for LRP in lipoprotein-supported ovarian granulosa cell steroidogenesis.
This study shows the tissue distribution of alpha 2MR/LRP as determined by
immunohistochemistry with specific monoclonal antibodies. The analysis revealed alpha 2MR/LRP-expression in a restricted spectrum of cell types, including neurons and astrocytes in the central nervous system, epithelial cells of the gastrointestinal tract, smooth muscle cells, fibroblasts, Leydig cells in testis, granulosa cells in ovary, and dendritic interstitial cells of kidney.
Zheng G, et al reported organ distribution in rats of two members of the low-density
lipoprotein receptor gene family, gp330 and LRP/alpa 2MR, and
the receptor-associated protein (RAP).
They investigated immunohistochemically the distribution in rats of the homologous
proteins gp330 and the LDL receptor-related protein (LRP/alpha 2MR), and a receptor-associated protein (RAP), and the sites to which soluble exogenous RAP
binds.
LRP/alpha 2MR was widely distributed in interstitial cells, notably in fibroblasts
and macrophages, and was also present in a selected group of epithelial or
specialized cells, including hepatocytes, adrenal cortical cells, follicular cells of
the ovary, cells of the choroid plexus, ciliary body, mesangial cells, and some
neurons. In certain cells, notably hepatocytes and adrenal cortical cells,
LRP/alpha 2MR was detected mainly on the surface.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Ireland JL, et al reported evidence for for autocrine or paracrine roles of {alpha}2-macroglobulin in regulation of estradiol production by granulosa cells and development of dominant follicles.
alpha2-Macroglobulin (alpha2-M) inhibits proteinases and modulates the actions of growth factors and cytokines. Despite the key roles proteinases, growth factors, and cytokines have in folliculogenesis, the role of alpha2-M in follicular development is unknown. Our objectives were to: a) determine if granulosa cells produce alpha2-M and have alpha2-M receptors, b) examine the effect of alpha2-M on estradiol production by granulosa cells, c) establish whether amounts of alpha2-M and alpha2-M receptors were altered during dominant non-ovulatory follicle development, and d) examine alpha2-M's mechanism of action. The results demonstrated that bovine granulosa cells contain 5.2 Kb and 15 Kb mRNAs, and 720 kDa and 500 kDa proteins that correspond respectively to sizes of mRNAs and proteins for alpha2-M and the alpha2-M receptor. Treatment of granulosa cells with alpha2-M resulted in a specific dose responsive increase in estradiol production. Cell viability, cell number, and the amount of aromatase in granulosa cells were not altered by alpha2-M. Treatment of granulosa cells with factors that bind alpha2-M or its receptor did not mimic alpha2-M action. Although intrafollicular amounts of alpha2-M remained unchanged, amounts of alpha2-M receptor in granulosa cells were strongly inversely associated with concentrations of estradiol in dominant and subordinate follicles. Based on these results, we concluded that alpha2-M may have autocrine or paracrine roles in granulosa cells potentially important for regulation of estradiol production and development of dominant follicles.