Inhibition of MMP-9 secretion by the anti-metastatic PSP94-derived peptide PCK3145 requires cell surface laminin receptor signaling

ABSTRACTLigand recognition by cell-surface receptors underlies development and immunity in both animals and plants. Modulating receptor signaling is critical for appropriate cellular responses but the mechanisms ensuring this are poorly understood. Here, we show that signaling by plant receptors for pathogen-associated molecular patterns (PAMPs) in immunity and CLAVATA3/EMBRYO SURROUNDING REGION-RELATED peptides (CLEp) in development employ a similar regulatory module. In the absence of ligand, signaling is dampened through association with specific type-2C protein phosphatases (PP2Cs). Upon activation, PAMP and CLEp receptors phosphorylate divergent cytosolic kinases, which, in turn, phosphorylate the phosphatases, thereby promoting their release from the receptor complexes. Our work reveals a regulatory circuit shared between immune and developmental receptor signaling, which may have broader important implications for plant receptor kinase-mediated signaling in general.

Download Full-text

Alteration of collagen-dependent adhesion, motility, and morphogenesis by the expression of antisense alpha 2 integrin mRNA in mammary cells

Journal of Cell Science ◽

10.1242/jcs.108.2.595 ◽

1995 ◽

Vol 108 (2) ◽

pp. 595-607 ◽

Cited By ~ 14

Author(s):

P.J. Keely ◽

A.M. Fong ◽

M.M. Zutter ◽

S.A. Santoro

Keyword(s):

Cell Surface ◽

Three Dimensional ◽

Cellular Growth ◽

Laminin Receptor ◽

Breast Carcinoma Cell Line ◽

Integrin Expression ◽

Mammary Cells ◽

Collagen Gels ◽

T47d Cells ◽

Beta 1 Integrin

Although integrins are known to mediate adhesive binding of cells to the extracellular matrix, their role in mediating cellular growth, morphology, and differentiation is less clear. To determine more directly the role of the alpha 2 beta 1 integrin, a collagen and laminin receptor, in mediating the collagen-dependent differentiation of mammary cells, we reduced expression of the integrin by the well differentiated human breast carcinoma cell line, T47D, by stably expressing alpha 2 integrin antisense mRNA. Flow cytometry demonstrated that the antisense-expressing clones had levels of alpha 2 beta 1 integrin on their surfaces that were decreased by 30–70%. Adhesion of antisense-expressing clones to both collagens I and IV was decreased relative to controls in a manner that correlated with the level of cell surface alpha 2 beta 1 integrin expression. Adhesion to fibronectin and laminin were not affected. Motility across collagen-coated filters in haptotaxis assays was increased for only those clones that exhibited intermediate levels of adhesion to collagen, suggesting that an intermediate density of cell-surface alpha 2 beta 1 integrin optimally supports cell motility. When cultured in three-dimensional collagen gels, T47D cells organized in a manner suggestive of a glandular epithelium. In contrast, antisense-expressing clones with decreased alpha 2 beta 1 integrin were not able to organize in three-dimensional collagen gels. The growth rate of T47D cells was reduced when the cells were cultured in three-dimensional collagen gels. Unlike adhesion, motility, and morphogenesis, growth rates were unaffected by reduction of alpha 2 beta 1 integrin expression. Our results suggest that adhesive interactions mediated by a critical level of surface alpha 2 beta 1 integrin expression are key determinants of the collagen-dependent morphogenetic capacity of mammary epithelial cells.

Download Full-text

EGCG down-regulates MuRF1 expression through 67-kDa laminin receptor and the receptor signaling is amplified by eriodictyol

Journal of Natural Medicines ◽

10.1007/s11418-020-01417-6 ◽

2020 ◽

Vol 74 (4) ◽

pp. 673-679 ◽

Cited By ~ 1

Author(s):

Motoki Murata ◽

Yuki Shimizu ◽

Yuki Marugame ◽

Ayaka Nezu ◽

Konatsu Fujino ◽

...

Keyword(s):

Laminin Receptor ◽

Receptor Signaling

Download Full-text

Serotonin Receptor Agonist 5-Nonyloxytryptamine Alters the Kinetics of Reovirus Cell Entry

Journal of Virology ◽

10.1128/jvi.00739-15 ◽

2015 ◽

Vol 89 (17) ◽

pp. 8701-8712 ◽

Cited By ~ 13

Author(s):

Bernardo A. Mainou ◽

Alison W. Ashbrook ◽

Everett Clinton Smith ◽

Daniel C. Dorset ◽

Mark R. Denison ◽

...

Keyword(s):

Cell Surface ◽

Small Molecule ◽

Receptor Agonist ◽

Serotonin Receptor ◽

Cell Entry ◽

Receptor Signaling ◽

Double Stranded Rna ◽

Reovirus Infection ◽

Small Molecule Screen ◽

Diverse Virus

ABSTRACTMammalian orthoreoviruses (reoviruses) are nonenveloped double-stranded RNA viruses that infect most mammalian species, including humans. Reovirus binds to cell surface glycans, junctional adhesion molecule A (JAM-A), and the Nogo-1 receptor (depending on the cell type) and enters cells by receptor-mediated endocytosis. Within the endocytic compartment, reovirus undergoes stepwise disassembly, which is followed by release of the transcriptionally active viral core into the cytoplasm. In a small-molecule screen to identify host mediators of reovirus infection, we found that treatment of cells with 5-nonyloxytryptamine (5-NT), a prototype serotonin receptor agonist, diminished reovirus cytotoxicity. 5-NT also blocked reovirus infection. In contrast, treatment of cells with methiothepin mesylate, a serotonin antagonist, enhanced infection by reovirus. 5-NT did not alter cell surface expression of JAM-A or attachment of reovirus to cells. However, 5-NT altered the distribution of early endosomes with a concomitant impairment of reovirus transit to late endosomes and a delay in reovirus disassembly. Consistent with an inhibition of viral disassembly, 5-NT treatment did not alter infection byin vitro-generated infectious subvirion particles, which bind to JAM-A but bypass a requirement for proteolytic uncoating in endosomes to infect cells. We also found that treatment of cells with 5-NT decreased the infectivity of alphavirus chikungunya virus and coronavirus mouse hepatitis virus. These data suggest that serotonin receptor signaling influences cellular activities that regulate entry of diverse virus families and provides a new, potentially broad-spectrum target for antiviral drug development.IMPORTANCEIdentification of well-characterized small molecules that modulate viral infection can accelerate development of antiviral therapeutics while also providing new tools to increase our understanding of the cellular processes that underlie virus-mediated cell injury. We conducted a small-molecule screen to identify compounds capable of inhibiting cytotoxicity caused by reovirus, a prototype double-stranded RNA virus. We found that 5-nonyloxytryptamine (5-NT) impairs reovirus infection by altering viral transport during cell entry. Remarkably, 5-NT also inhibits infection by an alphavirus and a coronavirus. The antiviral properties of 5-NT suggest that serotonin receptor signaling is an important regulator of infection by diverse virus families and illuminate a potential new drug target.

Download Full-text

Modulating Cell-Surface Receptor Signaling and Ion Channel Functions by In Situ Glycan Editing

Angewandte Chemie ◽

10.1002/ange.201706535 ◽

2018 ◽

Vol 130 (4) ◽

pp. 979-983 ◽

Cited By ~ 2

Author(s):

Hao Jiang ◽

Aimé López-Aguilar ◽

Lu Meng ◽

Zhongwei Gao ◽

Yani Liu ◽

...

Keyword(s):

Cell Surface ◽

Ion Channel ◽

Cell Surface Receptor ◽

Receptor Signaling ◽

Surface Receptor

Download Full-text

Modulating Cell-Surface Receptor Signaling and Ion Channel Functions by In Situ Glycan Editing

Angewandte Chemie International Edition ◽

10.1002/anie.201706535 ◽

2018 ◽

Vol 57 (4) ◽

pp. 967-971 ◽

Cited By ~ 11

Author(s):

Hao Jiang ◽

Aimé López-Aguilar ◽

Lu Meng ◽

Zhongwei Gao ◽

Yani Liu ◽

...

Keyword(s):

Cell Surface ◽

Ion Channel ◽

Cell Surface Receptor ◽

Receptor Signaling ◽

Surface Receptor

Download Full-text

Cell surface galactosyltransferase mediates the initiation of neurite outgrowth from PC12 cells on laminin.

The Journal of Cell Biology ◽

10.1083/jcb.110.2.461 ◽

1990 ◽

Vol 110 (2) ◽

pp. 461-470 ◽

Cited By ~ 67

Author(s):

P C Begovac ◽

B D Shur

Keyword(s):

Cell Surface ◽

Neurite Outgrowth ◽

Enzymatic Reaction ◽

Mesenchymal Cell ◽

Laminin Receptor ◽

Extracellular Matrix Molecule ◽

Neurite Initiation ◽

Neurite Formation ◽

And Migration

Neurite outgrowth from PC12 pheochromocytoma cells, as well as from peripheral and central nervous system neurons in vitro, is mediated by the extracellular matrix molecule, laminin. We have recently shown that mesenchymal cell spreading and migration on laminin is mediated, in part, by the cell surface enzyme, beta 1,4 galactosyltransferase (GalTase). GalTase is localized on lamellipodia of migrating cells where it functions as a laminin receptor by binding to specific N-linked oligosaccharides in laminin (Runyan et al., 1988; Eckstein and Shur, 1989). In the present study, we examined whether GalTase functions similarly during neutrite outgrowth on laminin using biochemical and immunological analyses. PC12 neurite outgrowth was inhibited by reagents that perturb cell surface GalTase activity, including anti-GalTase IgG and Fab fragments, as well as the GalTase modifier protein alpha-lactalbumin. Control reagents had no effect on neurite outgrowth. Furthermore, blocking GalTase substrates on laminin matrices by earlier galactosyltion or enzymatic removal of GalTase substrates also inhibited neurite outgrowth. Conversely, neurite outgrowth was enhanced by the addition of UDP-galactose, which completes the GalTase enzymatic reaction, while inappropriate sugar nucleotides had no effect. The effects of all these treatments were dose and/or time dependent. Surface GalTase was shown to function during both neurite initiation and elongation, although the effects of GalTase perturbation were most striking during the initiation stages of neurite formation. Consistent with this, surface GalTase was localized by indirect immunofluorescence to the growth cone and developing neurite. Collectively, these results demonstrate that GalTase mediates the initiation of neurite outgrowth on laminin, and to a lesser extent, neurite elongation. Furthermore, this study demonstrates that process extension from both mesenchymal cells and neuronal cells is partly dependent upon specific oligosaccharide residues in laminin.

Download Full-text