Functional Analyses of Two Cellular Binding Domains of Bovine Lactadherin

Andersen, Michael Brun; Graversen, Helle; Fedosov, Sergey N.; Petersen, Torben E.; Rasmussen, Jan T.

doi:10.1021/bi992221r

Cited by 192 publications

(196 citation statements)

References 33 publications

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“…Studies of MFG-E8 purified from milk suggest that it may function as a cell adhesion molecule by virtue of its two binding motifs: recognition of the RGD motif within the second EGF domain by ␣ v ␤ 5/3 integrins and binding of the discoidin/C domains to membrane phospholipids of mammary epithelial cells (5,14). Consequently, the adhesive behavior of SED1-null mammary epithelial cells was examined by using organoid cultures as well as quantitative single-cell adhesion assays.…”

Section: Sed1-null Epithelial Cells Show Defective Adhesionmentioning

confidence: 99%

The EGF repeat and discoidin domain protein, SED1/MFG-E8, is required for mammary gland branching morphogenesis

Ensslin

Shur

2007

Proc. Natl. Acad. Sci. U.S.A.

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SED1, also known as MFG-E8, is a secreted protein composed of two EGF repeats (the second of which contains an RGD motif) and two discoidin/Factor V/VIII C domains. SED1 is expressed by a wide range of cell types, where it participates in diverse cellular interactions, such as sperm binding to the egg coat and macrophage recognition of apoptotic lymphocytes. Although SED1 was originally identified as a milk protein, its function in the mammary gland remains unclear; suggested functions include inhibition of viral infection and clearance of apoptotic cells during mammary gland involution. We report here that SED1 has an unexpected obligatory role during mammary gland development. Unlike that seen in WT glands, SED1-null glands show severely reduced branching from epithelial ducts and from terminal end buds, which are thin and poorly developed. SED1 is expressed by both luminal and myoepithelial cells in the developing epithelial duct, and binds to ␣v integrin receptors on myoepithelial cells leading to MAPK activation and cell proliferation. The absence of SED1 leads to greatly reduced levels of activated MAPK and a concomitant reduction in cell proliferation and branching throughout the epithelial tree. These results suggest that SED1 contributes, at least partly, to the intercellular signaling between luminal and myoepithelial cells that is required for branching morphogenesis.cell adhesion ͉ epithelia ͉ integrins

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Section: Sed1-null Epithelial Cells Show Defective Adhesionmentioning

confidence: 99%

The EGF repeat and discoidin domain protein, SED1/MFG-E8, is required for mammary gland branching morphogenesis

Ensslin

Shur

2007

Proc. Natl. Acad. Sci. U.S.A.

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“…MFGE8/lactadherin binds to phosphatidylserine at the surface of membrane vesicles (Oshima et al, 2002;Veron et al, 2005) and apoptotic cells (Hanayama et al, 2002) through its FactorVIII-like domain (Shi et al, 2004), and exposes its EGF-like domain for recognition by avb3/b5 integrins (Andersen et al, 2000). MFGE8 displays three types of functions.…”

Section: Introductionmentioning

confidence: 99%

Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development

Sugano

Bernard‐Pierrot

et al. 2010

Oncogene

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Milk fat globule-epidermal growth factor-factor VIII (MFGE8), also called lactadherin or SED1, is a secreted integrin-binding protein that promotes elimination of apoptotic cells by phagocytes leading to tolerogenic immune responses, and vascular endothelial growth factor (VEGF)-induced angiogenesis: two important processes for cancer development. Here, by transcriptomic analysis of 228 biopsies of bladder carcinomas, we observed overexpression of MFGE8 during tumor development, correlated with expression of genes involved in cell adhesion or migration and in immune responses, but not in VEGF-mediated angiogenesis. To test whether MFGE8 expression was instrumental in bladder tumor development, or a simple consequence of this development, we used genetic ablation in a mouse model of carcinogen-induced bladder carcinoma. We showed that Mfge8 was also upregulated in mouse carcinoma, and that in its absence, Mfge8-deficient animals developed less advanced tumors. Angiogenesis was similar in carcinogen-treated Mfge8-expressing or -deficient bladders, thus ruling out a major role of the proangiogenic function of Mfge8 for its protumoral role. By contrast, the tumorpromoting role of Mfge8 was not observed anymore in mice devoid of adaptive immune system, and human tumors overexpressing MFGE8 where invaded with macrophages and regulatory T cells, thus suggesting that MFGE8/ lactadherin favors development of bladder tumors at least partly by an immune system-dependent mechanism. Our observations suggest future use of MFGE8-inhibiting molecules as therapies of bladder carcinomas, and of a limited number of other human cancers, in which our analysis of public databases also revealed overexpression of MFGE8.

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“…These homologous molecules contain an N-terminal EGFlike domain that harbors a RGD motif, and two C1 lipid-binding domains that bind externalized PS on the apoptotic cell [26]. Although MFG-E8 transmits outside to inside signals through αvβ5 or αvβ3 integrin to activate Rac1 [24,27], it is not known whether talin binding to the β5 cytoplasmic tail and integrin activation are required for MFG-E8 binding and the ensuing engulfment.…”

Section: Introductionmentioning

confidence: 99%

A NPxY-independent β5 integrin activation signal regulates phagocytosis of apoptotic cells

Singh

D’Mello

Henegouwen

et al. 2007

Biochemical and Biophysical Research Communications

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Integrin receptors are heterodimeric trans-membrane receptors with critical functions in cell adhesion and migration, cell cycle progression, differentiation, apoptosis, and phagocytosis of apoptotic cells. Integrins are activated by intracellular signaling that alter the binding affinity for extracellular ligands, so-called inside to outside signaling. A common element for integrin activation involves binding of the cytoskeletal protein talin, via its FERM domain, to a highly conserved NPxY motif in the beta chain cytoplasmic tails, which is involved in long-range conformation changes to the extracellular domain that impinges on ligand affinity. When the human beta-5 (β5) integrin cDNA was expressed in αv positive, β5 and β3 negative hamster CS-1 cells, it promoted NPxY-dependent adhesion to VTN-coated surfaces, phosphorylation of FAK, and concomitantly, β5 integrin-EGFP protein was recruited into talin and paxillin-containing focal adhesions. Expression of a NPxY destabilizing β5 mutant (Y750A) abrogated adhesion and β5-Y750A-EGFP was excluded from focal adhesions at the tips of stress fibers. Surprisingly, expression of β5 Y750A integrin had a potent gainof-function effect on apoptotic cell phagocytosis, and further, a β5-Y750A EGFP fusion integrin readily bound MFG-E8-coated 10 um diameter microspheres developed as apoptotic cell mimetics. The critical sequences in β5 integrin were mapped to a YEMAS motif just proximal to the NPxY motif. Our studies suggest that the phagocytic function of β5 integrin is regulated by an unconventional NPxY-talin independent activation signal and argue for the existence of molecular switches in the β5 cytoplasmic tail for adhesion and phagocytosis.

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Functional Analyses of Two Cellular Binding Domains of Bovine Lactadherin

Cited by 192 publications

References 33 publications

The EGF repeat and discoidin domain protein, SED1/MFG-E8, is required for mammary gland branching morphogenesis

The EGF repeat and discoidin domain protein, SED1/MFG-E8, is required for mammary gland branching morphogenesis

Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development

A NPxY-independent β5 integrin activation signal regulates phagocytosis of apoptotic cells

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