Ganglioside GM2-Tetraspanin CD82 Complex Inhibits Met and Its Cross-talk with Integrins, Providing a Basis for Control of Cell Motility through Glycosynapse

Todeschini, Adriane R.; Santos, Jose Nilson Dos; Handa, Kazuko; Hakomori, Sen‐itiroh

doi:10.1074/jbc.m611407200

Cited by 134 publications

(135 citation statements)

References 54 publications

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“…G D1a inhibits HGF-induced motility and scattering of cancer cells through suppression of tyrosine phosphorylation of c-Met (33). G M3 and G M2 form heterodimers that specifically interact with tetraspanin (CD82) in glycosynapses, and such complexes inhibit c-Met activation and integrin cross talk (34,35). However, to our knowledge, it is the first demonstration of ganglioside-induced c-Met constitutive activation in cancer cells.…”

Section: Discussionmentioning

confidence: 81%

GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

Cazet

Lefebvre

Adriaenssens

et al. 2010

Molecular Cancer Research

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The disialoganglioside G D3 is overexpressed in ∼50% of invasive ductal breast carcinoma, and the G D3 synthase gene (ST8SIA1) displays higher expression among estrogen receptor-negative breast cancer tumors, associated with a decreased overall survival of breast cancer patients. However, no relationship between ganglioside expression and breast cancer development and aggressiveness has been reported. We have previously shown that overexpression of G D3 synthase induces the accumulation of b-and c-series gangliosides (G D3 , G D2 , and G T3 ) at the cell surface of MDA-MB-231 breast cancer cells together with the acquisition of a proliferative phenotype in the absence of serum. Here, we show that phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways are constitutively activated in G D3 synthaseexpressing cells. Analysis of phosphorylation of tyrosine kinase receptors shows a specific c-Met constitutive activation in G D3 synthase-expressing cells, in the absence of its ligand, hepatocyte growth factor/scatter factor. In addition, inhibition of c-Met or downstream signaling pathways reverses the proliferative phenotype. We also show that G D3 synthase expression enhances tumor growth in severe combined immunodeficient mice. Finally, a higher expression of ST8SIA1 and MET in the basal subtype of human breast tumors are observed. Altogether, our results show that G D3 synthase expression is sufficient to enhance the tumorigenicity of MDA-MB-231 breast cancer cells through a ganglioside-dependent activation of the c-Met receptor.

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Section: Discussionmentioning

confidence: 81%

GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

Cazet

Lefebvre

Adriaenssens

et al. 2010

Molecular Cancer Research

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“…In contrast to these previous studies, focused on GM3-CD9 interaction that inhibits tumor cell motility, our recent studies (9) addressed the functional role of the GM2/CD82 complex that inhibits (i) hepatocyte growth factor (HGF)-induced cMet tyrosine kinase and (ii) laminin-5-mediated activation of ␣3 and its cross-talk with cMet tyrosine kinase, leading to inhibition of cell motility and growth.…”

mentioning

confidence: 75%

“…Thus, various cell adhesion processes mediated by GSLs and TSP cause extensive phenotypic changes, including reversion from malignant to normal cell phenotype (8,9,25). In analogy, Bissell and colleagues (26,27) showed that functional antibodies directed to ␤1 integrin of breast cancer cells caused reversion, in vitro and in vivo, to normal cellular organization, indicating that malignancy may arise from disorganization of glycosynaptic microdomain rather than from changes in gene structure and expression.…”

Section: Discussionmentioning

confidence: 99%

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Ganglioside GM2/GM3 complex affixed on silica nanospheres strongly inhibits cell motility through CD82/cMet-mediated pathway

Todeschini

Santos

Handa

et al. 2008

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

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115

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Ganglioside GM2 complexed with tetraspanin CD82 in glycosynaptic microdomain of HCV29 and other epithelial cells inhibits hepatocyte growth factor-induced cMet tyrosine kinase. In addition, adhesion of HCV29 cells to extracellular matrix proteins also activates cMet kinase through ''cross-talk '' of integrins with cMet, leading to inhibition of cell motility and growth. Present studies indicate that cell motility and growth are greatly influenced by expression of GM2, GM3, or GM2/GM3 complexes, which affect cMet kinase activity of various types of cells, based on the following series of observations: (i) Cells expressing CD82, cultured with GM2 and GM3 cocoated on silica nanospheres, displayed stronger and more consistent motility inhibition than those cultured with GM2 or GM3 alone or with other glycosphingolipids. (ii) GM2-GM3, in the presence of Ca 2؉ form a heterodimer, as evidenced by electrospray ionization (ESI) mass spectrometry and by specific reactivity with mAb 8E11, directed to GM2/GM3 dimer structure. (iii) Cells expressing cMet and CD82 were characterized by enhanced motility associated with HGF-induced cMet activation. Both cMet and motility were strongly inhibited by culturing cells with GM2/GM3 dimer coated on nanospheres. (iv) Adhesion of HCV29 or YTS-1/CD82 cells to laminin-5-coated plate activated cMet kinase in the absence of HGF, whereas GM2/GM3 dimer inhibited adhesioninduced cMet kinase activity and inhibited cell motility. (v) Inhibited cell motility as in i, iii, and iv was restored to normal level by addition of mAb 8E11, which blocks interaction of GM2/GM3 dimer with CD82. Signaling through Src and MAP kinases is activated or inhibited in close association with cMet kinase, in response to GM2/GM3 dimer interaction with CD82. Thus, a previously uncharacterized GM2/GM3 heterodimer complexed with CD82 inhibits cell motility through CD82-cMet or integrin-cMet pathway.glycosphingolipid ͉ growth factor receptor ͉ ldlD cells ͉ tyrosine kinase G lycosphingolipids (GSLs), including gangliosides, interact with specific membrane proteins, such as growth factor receptors, integrins, tetraspanins (TSPs), and nonreceptor cytoplasmic kinases (e.g., Src family kinases and small G proteins), to form glycosynaptic microdomains controlling GSL-dependent or -modulated cell adhesion, growth, and motility (for review, see refs. 1-3).Our previous studies indicate the following: (i) Ganglioside the GM3/TSP CD9 complex interacts with integrin ␣3␤1 or ␣5␤1 and inhibits motility of CD9-expressing tumor cells (4, 5). (ii) The GM3/CD9/CD81 complex inhibits tyrosine kinase associated with fibroblast growth factor receptor (FGFR) (6) and blocks functional interaction of integrins with FGFR (7). (iii) Enhancement of GM3 or CD9 level in bladder cancer cell line YTS-1 causes reversion to normal phenotype, whereby Src kinase activity is strongly inhibited (8).In contrast to these previous studies, focused on GM3-CD9 interaction that inhibits tumor cell motility, our recent studies (9) addressed the functional role of t...

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“…The activities of phospholipase C␥-1 and a variety of Src kinases can be similarly demonstrated to be dramatically affected by genetic or pharmacologic manipulations of cellular glycosphingolipids (9,10). Recently, it has been reported that these changes may be mediated by the direct binding of tetraspanins to membrane glycosphingolipids as part of a larger structure termed a glycosynapse (23). These observations beg an important question, namely, do specific glycosphingolipids and changes in their relative concentrations regulate specific signaling phenomena?…”

Section: Discussionmentioning

confidence: 98%

Caveolin-associated Accumulation of Globotriaosylceramide in the Vascular Endothelium of α-Galactosidase A Null Mice

Shu

Shayman

2007

Journal of Biological Chemistry

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Ganglioside GM2-Tetraspanin CD82 Complex Inhibits Met and Its Cross-talk with Integrins, Providing a Basis for Control of Cell Motility through Glycosynapse

Cited by 134 publications

References 54 publications

GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

Ganglioside GM2/GM3 complex affixed on silica nanospheres strongly inhibits cell motility through CD82/cMet-mediated pathway

Caveolin-associated Accumulation of Globotriaosylceramide in the Vascular Endothelium of α-Galactosidase A Null Mice

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