Mutation at tyrosine residue 1337 abrogates ligand-dependent transforming capacity of the FLT4 receptor.
In humans, the FLT4 gene encodes two isoforms of a tyrosine kinase receptor, which differ in their carboxy terminal regions. As compared to the short form, the long form has an additional stretch of 65 amino acids containing three tyrosine residues (Y1333, Y1337 and Y1363). Once expressed in fibroblast cells, only the long form is able to elicit both anchorage-independent growth in a soft agar assay and tumors in nude mice, and thus appears endowed with a potential ligand-dependent transforming capacity. Replacement of tyrosine 1337 by phenylalanine abrogates the transforming capacity of the long form. This residue was identified as a potential autophosphorylation site, and a docking site for a substrate important in the signal transduction specific of the long FLT4 isoform. We demonstrate that the GRB2 and SHC cytoplasmic substrates are involved in FLT4 signal transduction. SHC interaction could be crucial to FLT4-mediated transforming activity associated with the long isoform. Finally, trancripts for the two forms are detected in tissues positive for FLT4 gene expression.
Fournier
E
E
Laboratoire d'Oncologie moléculaire, U.119 INSERM, Marseille, France.
Dubreuil
P
P
Birnbaum
D
D
Borg
J P
JP
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D051380:GRB2 Adaptor Protein; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship; D014443:Tyrosine; D040321:Vascular Endothelial Growth Factor Receptor-3
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; C495950:Grb2 protein, rat; D008024:Ligands; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014443:Tyrosine; D020794:Receptor Protein-Tyrosine Kinases; D040321:Vascular Endothelial Growth Factor Receptor-3