title: Deacetylated GM3 promotes uPAR-associated membrane molecular complex to activate p38 MAPK in metastatic melanoma.
abstract: GM3, the simplest ganglioside, regulates cell proliferation, migration, and invasion by influencing cell signaling at the membrane level. Although the classic N-acetylated form of GM3 (NeuAcLacCer) is commonly expressed and has been well studied, deacetylated GM3 (NeuNH2LacCer, d-GM3) has been poorly investigated, despite its presence in metastatic tumors but not in noninvasive melanomas or benign nevi. We have recently found that d-GM3 stimulates cell migration and invasion by activating urokinase plasminogen activator receptor (uPAR) signaling to augment matrix metalloproteinase-2 (MMP-2) function. However, the mechanisms by which d-GM3/uPAR increase MMP-2 expression and activation are not clear. By modifying the expression of d-GM3 genetically and biochemically, we found that decreasing d-GM3 expression inhibits, whereas overexpressing d-GM3 stimulates, p38 mitogen-activated protein kinase (MAPK) activity to influence MMP-2 expression and activation. p38 MAPK (p38) activation requires the formation of a membrane complex that contains uPAR, caveolin-1, and integrin α5β1 in membrane lipid rafts. In addition, knocking down or inhibiting focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), or Src kinase significantly reduces d-GM3-induced p38 phosphorylation and activation. Taken together, these results suggest that d-GM3 enhances the metastatic phenotype by activating p38 signaling through uPAR/integrin signaling with FAK, PI3K, and Src kinase as intermediates. Elucidation of the mechanisms by which d-GM3, a newly discovered, potential biomarker of metastatic melanomas, promotes cell metastasis will help us to understand the function of d-GM3 in metastatic melanomas and may lead to novel GM3-based cancer therapies.
authors.affiliation: Department of Dermatology and Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Yan
authors.forename: Daniel Q
authors.initials: DQ
authors.lastname: Bach
authors.forename: Nandita
authors.initials: N
authors.lastname: Gatla
authors.forename: Ping
authors.initials: P
authors.lastname: Sun
authors.forename: Ji-Wei
authors.initials: JW
authors.lastname: Liu
authors.forename: Jian-Yun
authors.initials: JY
authors.lastname: Lu
authors.forename: Amy S
authors.initials: AS
authors.lastname: Paller
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D005679:G(M3) Ganglioside / Q000494:pharmacology*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D012799:Sialyltransferases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D005679:G(M3) Ganglioside; D039081:Integrin alpha5beta1; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D012799:Sialyltransferases; C021343:haematoside synthetase; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2