Interactions between a Receptor Tyrosine Phosphatase and a Cell Surface Ligand Regulate Axon Guidance and Glial-Neuronal Communication

AbstractGlypican-3 (GPC3) is a cell surface heparan sulfate proteoglycan that is being evaluated as an emerging therapeutic target in hepatocellular carcinoma (HCC). GPC3 has been shown to interact with several extracellular signaling molecules, including Wnt, HGF, and Hedgehog. Here, we reported a cell surface transmembrane protein (FAT1) as a new GPC3 interacting protein. The GPC3 binding region on FAT1 was initially mapped to the C-terminal region (Q14517, residues 3662-4181), which covered a putative receptor tyrosine phosphatase (RTP)-like domain, a Laminin G-like domain, and five EGF-like domains. Fine mapping by ELISA and flow cytometry showed that the last four EGF-like domains (residues 4013-4181) contained a specific GPC3 binding site, whereas the RTP domain (residues 3662-3788) and the downstream Laminin G-2nd EGF-like region (residues 3829-4050) had non-specific GPC3 binding. In support of their interaction, GPC3 and FAT1 behaved concomitantly or at a similar pattern, e.g. having elevated expression in HCC cells, being up-regulated under hypoxia conditions, and being able to regulate the expression of EMT-related genes Snail, Vimentin, and E-Cadherin and promoting HCC cell migration. Taken together, our study provides the initial evidence for the novel mechanism of GPC3 and FAT1 in promoting HCC cell migration.

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A generic cell surface ligand system for studying cell-cell recognition

10.1101/546846 ◽

2019 ◽

Author(s):

Eleanor M Denham ◽

Michael I Barton ◽

Susannah M Black ◽

Marcus J Bridge ◽

Ben de Wet ◽

...

Keyword(s):

Cell Surface ◽

Surface Density ◽

Cell Receptor ◽

Surface Receptors ◽

Ligand System ◽

Ligand Interactions ◽

A Cell ◽

Surface Ligand ◽

Receptor Biology ◽

Cell Cell

AbstractDose-response experiments are a mainstay of receptor biology studies and can reveal valuable insights into receptor function. Such studies of receptors that bind cell surface ligands are currently limited by the difficulty in manipulating the surface density of ligands at a cell-cell interface. Here we describe a generic cell surface ligand system that allows precise manipulation of cell surface ligand densities over several orders of magnitude. We validate the system for a range of immunoreceptors, including the T cell receptor (TCR), and show that this generic ligand stimulates via the TCR at a similar surface density as its native ligand. This system allows the effect of surface density, valency, dimensions, and affinity of the ligand to be manipulated. It can be readily extended to other receptor-cell surface ligand interactions, and will facilitate investigation into the activation of, and signal integration between, cell surface receptors.

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Gingipains Inactivate a Cell Surface Ligand onPorphyromonas gingivalisThat Induces TLR2- and TLR4-Independent Signaling

Microbiology and Immunology ◽

10.1111/j.1348-0421.2006.tb03799.x ◽

2006 ◽

Vol 50 (4) ◽

pp. 315-325 ◽

Cited By ~ 8

Author(s):

Mami Kishimoto ◽

Atsutoshi Yoshimura ◽

Mariko Naito ◽

Kuniaki Okamoto ◽

Kenji Yamamoto ◽

...

Keyword(s):

Cell Surface ◽

A Cell ◽

Surface Ligand

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PTP1B Modulates the Association of β-Catenin with N-cadherin through Binding to an Adjacent and Partially Overlapping Target Site

Journal of Biological Chemistry ◽

10.1074/jbc.m206454200 ◽

2002 ◽

Vol 277 (51) ◽

pp. 49989-49997 ◽

Cited By ~ 64

Author(s):

Gang Xu ◽

Carlos Arregui ◽

Jack Lilien ◽

Janne Balsamo

Keyword(s):

Amino Acids ◽

Cell Surface ◽

Tyrosine Phosphatase ◽

Target Site ◽

Target Domain ◽

Chick Retina ◽

Cell Permeable Peptide ◽

A Cell ◽

Relationship Of

The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of β-catenin. We have now identified the domain on N-cadherin to which PTP1B binds and characterized the effect of perturbing this domain on cadherin function. Deletion constructs lacking amino acids 872–891 fail to bind PTP1B. This domain partially overlaps with the β-catenin binding domain. To further define the relationship of these two sites, we used peptides to competein vitrobinding. A peptide representing the most NH2-terminal 8 amino acids of the PTP1B binding site, the region of overlap with the β-catenin target, effectively competes for binding of β-catenin but is much less effective in competing PTP1B, whereas two peptides representing the remaining 12 amino acids have no effect on β-catenin binding but effectively compete for PTP1B binding. Introduction into embryonic chick retina cells of a cell-permeable peptide mimicking the 8 most COOH-terminal amino acids in the PTP1B target domain, the region most distant from the β-catenin target site, prevents binding of PTP1B, increases the pool of free, tyrosine-phosphorylated β-catenin, and results in loss of N-cadherin function. N-cadherin lacking this same region of the PTP1B target site does not associate with PTP1B or β-catenin and is not efficiently expressed at the cell surface of transfected L cells. Thus, interaction of PTP1B with N-cadherin is essential for its association with β-catenin, stable expression at the cell surface, and consequently, cadherin function.

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