Growth factor-dependent phosphorylation of the actin-binding protein cortactin is mediated by the cytoplasmic tyrosine kinase FER.
Previous characterization of the nonreceptor tyrosine kinase FER identified a tight physical association with the catenin pp120 and led to the suggestion that FER may be involved in cell-cell signaling. To further understand the function of FER, we have continued our analyses of the interaction of FER with pp120 and other proteins. The majority of FER is localized to the cytoplasmic fraction where it forms a complex with the actin-binding protein cortactin. The Src homology 2 sequence of FER is required for directly binding cortactin, and phosphorylation of the FER-cortactin complex is up-regulated in cells treated with peptide growth factors. Using a dominant-negative mutant of FER, we provided evidence that FER kinase activity is required for the growth factor-dependent phosphorylation of cortactin. These data suggest that cortactin is likely to be a direct substrate of FER. Our observations provide additional support for a role of FER in mediating signaling from the cell surface, via growth factor receptors, to the cytoskeleton. The nature of the FER-cortactin interaction, and their putative enzyme-substrate relationship, support the previous proposal that one of the functions of the Src homology 2 sequences of nonreceptor tyrosine kinases is to provide a binding site for their preferred substrates.
Department of Biochemistry, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
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D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000918:Antibody Specificity; D001665:Binding Sites; D002451:Cell Compartmentation; D002458:Cell Fractionation; D051356:Cortactin; D003593:Cytoplasm / Q000201:enzymology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D018909:src Homology Domains
C495868:CTTN protein, human; D051356:Cortactin; C495869:Cttn protein, mouse; D003598:Cytoskeletal Proteins; D008840:Microfilament Proteins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C052602:proto-oncogene protein c-fes-fps; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases