Identification of rat yolk sac target protein of teratogenic antibodies, gp280, as intrinsic factor-cobalamin receptor.

Seetharam, Bellur; Christensen, Erik; Moestrup, Søren K.; Hammond, Timothy G.; Verroust, P

doi:10.1172/jci119411

Cited by 116 publications

(73 citation statements)

References 26 publications

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“…16 Indirect evidence for cubilin playing a similar role in ligand transcytosis comes from findings showing that albumin is transcytosed back to circulation via the proximal tubule epithelium, [17][18][19] as well as the fact that cubilin-mediated uptake of intrinsic factor-B 12 complex in the gut leads to its release into blood in the form of transcobalamin-B 12 . 20 Whether or not renal cubilin-mediated uptake of apoA-I and albumin from the glomerular filtrate might be part of a salvage process that affects levels of these proteins in the blood is not known. Here, we sought to define the relationships between genetic cubilin deficiency and renal uptake/urinary loss of apoA-I and albumin, along with the extent to which cubilin deficiency influences blood levels of each constituent, as well as HDL.…”

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confidence: 99%

Cubilin Maintains Blood Levels of HDL and Albumin

Aseem

Smith

Cooley

et al. 2014

Journal of the American Society of Nephrology

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Cubilin is an endocytic receptor highly expressed in renal proximal tubules, where it mediates uptake of albumin and filtered forms of apoA-I/HDL. Cubilin deficiency leads to urinary loss of albumin and apoA-I; however, the consequences of cubilin loss on the homeostasis of blood albumin and apoA-I/HDL have not been studied. Using mice heterozygous for cubilin gene deletion (cubilin HT mice), we show that cubilin haploinsufficiency leads to reduced renal proximal tubular uptake of albumin and apoA-I and significantly increased urinary loss of albumin and apoA-I. Moreover, cubilin HT mice displayed significantly decreased blood levels of albumin, apoA-I, and HDL. The levels of albumin and apoA-I protein or mRNA expressed in the liver, kidney, or intestine of cubilin HT mice did not change significantly. The clearance rate of small HDL 3 particles (density.1.13 g/ml) from the blood increased significantly in cubilin HT mice. In contrast, the rate of clearance of larger HDL 2 particles from the blood did not change significantly, indicating a decreased half-life for HDL particles capable of filtering through the glomerulus. On the basis of these findings, we conclude that cubilin deficiency reduces renal salvage and delivery back to the blood of albumin and apoA-I, which decreases blood levels of albumin and apoA-I/HDL. These findings raise the possibility that therapeutic increase of renal cubilin expression might reduce proteinuria and increase blood levels of albumin and HDL.

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confidence: 99%

Cubilin Maintains Blood Levels of HDL and Albumin

Aseem

Smith

Cooley

et al. 2014

Journal of the American Society of Nephrology

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“…C ubilin, which is also known as the intrinsic factorcobalamin (IF-B12) receptor (1), is a multiligand receptor expressed at the apical plasma membrane and in endocytic compartments of several absorptive epithelia, especially the kidney proximal tubule, the small intestine, and the visceral yolk sac, where it plays a scavenger receptor function, in concert with megalin (2)(3)(4)(5). Mutations in the cubilin gene have been identified in a group of patients who have Imerslund-Gräsbeck's syndrome (or megaloblastic anemia type 1) (6,7), a rare genetic disorder characterized by defective intestinal absorption of vitamin B 12 and proteinuria.…”

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confidence: 99%

Contribution of Cubilin and Amnionless to Processing and Membrane Targeting of Cubilin–Amnionless Complex

Coudroy¹,

Gburek²,

Kozyraki³

et al. 2005

Journal of the American Society of Nephrology

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Cubilin is a peripheral apical membrane receptor for multiple ligands that are taken up in several absorptive epithelia. Recently, amnionless (AMN) was identified to form a functional receptor complex with cubilin. By expression in transfected polarized MDCK cells of AMN and several cubilin fragments, including a functional "mini" version of cubilin, the processing, sorting, and membrane anchoring of the complex to the apical membrane were investigated. The results show that truncation mutants, including the N-terminal domain of cubilin, did not appear at the plasma membrane but instead were retained in the endoplasmic reticulum or partially secreted into the medium. Coexpression with AMN led to efficient transport to the apical cell surface of the cubilin constructs, which included the EGF domains, and prevented release into the medium. AMN co-precipitated with cubilin and co-localized with cubilin at the apical cell surface. Apical sorting was observed for a broad set of nonoverlapping cubilin fragments without the N-terminal region, in the absence of AMN. The preference for apical sorting disappeared when glycosylation was inhibited by tunicamycin. In conclusion, it is shown that both units contribute to the processing of the cubilin-AMN complex to the apical membrane: AMN interacts with the EGF domains of cubilin and is responsible for membrane attachment and export of the complex from the endoplasmic reticulum, whereas the extracellular cubilin molecule is responsible for apical sorting of the complex in a carbohydrate-dependent manner.

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“…In this earlier work, it was found that antibodies raised against yolk sac or kidney and administered to pregnant rats (27) or anti-p400 against mouse cubilin administered to pregnant mice 2 during the period of organogenesis resulted in severe fetal abnormalities and death. Although the mechanism responsible for the pathological effect of the antibodies is unknown, they localized in yolk sac epithelium, possibly inhibiting the endocytic apparatus in those cells (25)(26)(27). Since rodent yolk sac is the major portal for maternalfetal exchange prior to development of chorioallantoic circulation (28), it is presumed that disruption of transport of nutrients, such as maternal serum proteins, vitamin B 12 , and cholesterol-containing lipoproteins, during the critical phase of organogenesis could be involved (12,25,29).…”

Section: Discussionmentioning

confidence: 99%

Cubilin, a Binding Partner for Galectin-3 in the Murine Utero-Placental Complex

Crider-Pirkle¹,

Billingsley²,

Faust³

et al. 2002

Journal of Biological Chemistry

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Galectin-3 is a lectin important in animal development and regulatory processes and is found selectively localized at the implantation site of the mouse embryo. To better understand the role of galectin-3 at the maternal-fetal interface, a binding partner was isolated and characterized. Homogenates of uteroplacental tissue were incubated with immobilized recombinant galectin-3, and specifically bound proteins were eluted using lactose. The principal protein, p400, had an M r of 400,000 in SDS-PAGE. Physical properties of p400 and amino acid sequences of seven tryptic peptides were similar to cubilin from rats, humans, and dogs, identifying p400 as the murine ortholog of cubilin. This was further supported by the tissue distribution observed only in yolk sac, kidney, and ileum with monospecific antiserum for p400. Cubilin occurred in yolk sac epithelium throughout pregnancy, but galectin-3 was there only during the last week. Unexpectedly, cubilin was found only in perforin-containing granules of uterine natural killer (uNK) cells, although galectin-3 occurred throughout the cell cytoplasm. In situ hybridization revealed cubilin mRNA in yolk sac epithelium but not uNK cells, implying that yolk sac-derived cubilin is endocytosed by uNK cells via galectin-3. This is consistent with cubilin being an endogenous partner of galectin-3 at the maternal-fetal interface and suggests an important role for cubilin in uNK cell function. 1 is one of at least 10 members of a lectin family, which share a conserved carbohydrate recognition domain and which exert their varied biological effects through interaction with complementary ␤-galactoside ligands of glycoprotein or glycolipid "counterreceptors." Since galectins are divalent and are able to form multivalent aggregates, they can cross-link counterreceptors, effecting cell-cell, cell-matrix, or matrix-matrix interactions, thus possibly initiating signal transduction. Isolation of several membrane or matrix counterreceptors by affinity chromatography has revealed that galectins are linked to a variety of important processes including neoplastic transformation, cell adhesion, tumor invasiveness and metastasis, cellular proliferation, and localized immunomodulation (see Ref. 1). gal-3 and its mRNA are expressed in trophoblast cells of placenta as well as in the granular uNK cells of the metrial gland and decidualized endometrium of the murine implantation site (2-4). That finding, along with the additional observation that gal-3 is absent from nondecidualized endometrium between implantation sites and is not present in uteri of nonpregnant females (3), strongly suggests that this lectin has a pregnancy-related function at the maternalfetal interface. Although a role for gal-3 at the maternal-fetal interface is not yet known, it may contribute in some fashion to cell adhesion, proliferation, or immunomodulation, all of which occur in other contexts. Therefore, to gain more insight into a role for this lectin at the maternal-fetal interface, we isolated and characterized a counte...

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Identification of rat yolk sac target protein of teratogenic antibodies, gp280, as intrinsic factor-cobalamin receptor.

Cited by 116 publications

References 26 publications

Cubilin Maintains Blood Levels of HDL and Albumin

Cubilin Maintains Blood Levels of HDL and Albumin

Contribution of Cubilin and Amnionless to Processing and Membrane Targeting of Cubilin–Amnionless Complex

Cubilin, a Binding Partner for Galectin-3 in the Murine Utero-Placental Complex

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