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Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

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Author

  • Johan Lennartsson
  • Peter Blume-Jensen
  • Monica Hermanson
  • Emma Pontén
  • Monica Carlberg
  • Lars Rönnstrand

Summary, in English

In this report we show that Tyr568 and Tyr570 are phosphorylated in vivo in the Kit/stem cell factor receptor (Kit/SCFR) following ligand-stimulation. By mutation of Tyr568 and Tyr570 to phenylalanine residues and expression of the mutated receptors in porcine aortic endothelial (PAE) cells, we could demonstrate a loss of activation of members of the Src family of tyrosine kinases when Tyr568 was mutated, while mutation of Tyr570 only led to a minor decrease in activation of Src family members. Mutation of both tyrosine residues led to a complete loss of Src family kinase activation. Phosphorylation of the adapter protein Shc by growth factor receptors provides association sites for Grb2-Sos, thereby activating the Ras/MAP kinase pathway. A much lowered degree of Shc phosphorylation, Ras and Erk2 activation and c-fos induction was seen in the Y568F mutant, while in the Y570F mutant these responses were less affected. In contrast, the mitogenic response was only slightly reduced. In a mutant receptor with both Tyr568 and Tyr570 mutated to phenylalanine residues, no phosphorylation of Shc and no activation of Ras and Erk2 was seen in response to stem cell factor stimulation, very weak induction of c-fos was seen and the mitogenic response was severely depressed. These data show that Ras/MAP kinase activation and c-fos induction by Kit/SCFR are mediated by members of the Src family kinases. However, the mitogenic response is only to a minor extent dependent on Src kinase activity.

Publishing year

1999

Language

English

Pages

5546-5553

Publication/Series

Oncogene

Volume

18

Issue

40

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Medicinal Chemistry

Keywords

  • Vascular/drug effects/metabolism Enzyme Activation *Gene Expression Regulation *Genes
  • *Adaptor Proteins
  • Signal Transducing *Adaptor Proteins
  • fos Humans Ligands MAP Kinase Signaling System/*physiology Mitogen-Activated Protein Kinase 1/*metabolism Molecular Sequence Data Mutagenesis
  • Post-Translational Proteins/*physiology Proto-Oncogene Proteins c-kit/*physiology Proto-Oncogene Proteins p21(ras)/*metabolism Recombinant Fusion Proteins/metabolism/pharmacology Shc Signaling Adaptor Proteins Stem Cell Factor/pharmacology/physiology Swine src-Family Kinases/*physiology
  • Site-Directed Phosphorylation Phosphotyrosine/physiology *Protein Processing
  • Vesicular Transport Amino Acid Sequence Amino Acid Substitution Animals Aorta/cytology Cell Division/drug effects Cells
  • Cultured Endothelium

Status

Published

ISBN/ISSN/Other

  • ISSN: 1476-5594