title: Alpha 1,3-fucosyltransferase-VII regulates the signaling molecules of the insulin receptor pathway.
abstract: Two H7721 human hepatocarcinoma cell lines showing moderate and high expression of alpha1,3-fucosyltransferase (FucT)-VII cDNA were established and designated FucTVII-M and FucTVII-H, respectively. In alpha1,3-FucT-VII-transfected cells, expression of insulin receptor (InR) alpha- and beta subunits and epidermal growth factor receptor (EGFR) on the cell surface and in cells, as well as the sialyl Lewis X (SLe(x), the product of alpha1,3-FucT-VII) content of the EGFR were unchanged. However the level of SLe(x) on the InR alpha subunit (InR-alpha) was increased dramatically. Tyrosine autophosphorylation of InR-beta , but not EGFR, was elevated. Concomitantly, tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), Ser/Thr phosphorylation of protein kinase B (PKB; Akt), p42/44 mitogen-activated protein kinase (MAPK), MAPK kinase (MEK), and the protein of some other signaling molecules, such as phosphoinositide-dependent kinase-1 (PDK-1), novel protein kinase (PKN), c-Raf-1 and beta-catenin were also upregulated. The activities of PKB and transcription factor TCF were concomitantly stimulated. Upregulation of InR signaling molecules and their phosphorylation was correlated with the level of SLe(x) on InR-alpha and alpha1,3-FucT-VII expression in cells. In addition, the phosphorylation intensity and difference in phosphorylation intensity between cells with different levels of alpha1,3-FucT-VII expression were attenuated significantly by the inhibitor of InR tyrosine kinase and by the mAb to SLe(x). Furthermore, insulin-induced signaling was facilitated in alpha1,3-FucT-VII-transfected cells, particularly FucTVII-H. These findings provide strong evidence that alpha1,3-FucT-VII may affect insulin signaling by upregulating the phosphorylation and expression of some signaling molecules involved in the InR-signaling pathway. These effects are likely mediated by its product, SLe(x), on the glycans of the InR. This is the first study to report that changes in the terminal structure of glycans on a surface receptor can modify cell signaling.
authors.affiliation: Key Laboratory of Glycoconjugate Research, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Qiu-yan
authors.initials: QY
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hai-jiao
authors.initials: HJ
authors.lastname: Chen
authors.forename: Zong-hou
authors.initials: ZH
authors.lastname: Shen
authors.forename: Hui-li
authors.initials: HL
authors.lastname: Chen
mesh_terms: D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D005647:Fucosyltransferases / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009844:Oligosaccharides / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D000080506:Sialyl Lewis X Antigen; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry; D051176:beta Catenin / Q000378:metabolism
chemical_list: D007328:Insulin; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; D051820:TCF Transcription Factors; D051176:beta Catenin; D014443:Tyrosine; C502597:FUT7 protein, human; D005647:Fucosyltransferases; D066246:ErbB Receptors; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt