PMID- 10523831
OWN - NLM
STAT- MEDLINE
DCOM- 19991105
LR  - 20161124
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 18
IP  - 40
DP  - 1999 Sep 30
TI  - 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.
PG  - 5546-53
AB  - 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.
FAU - Lennartsson, J
AU  - Lennartsson J
AD  - The Ludwig Institute for Cancer Research, Biomedical Centre, S-751 24 Uppsala,
      Sweden.
FAU - Blume-Jensen, P
AU  - Blume-Jensen P
FAU - Hermanson, M
AU  - Hermanson M
FAU - Ponten, E
AU  - Ponten E
FAU - Carlberg, M
AU  - Carlberg M
FAU - Ronnstrand, L
AU  - Ronnstrand L
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Ligands)
RN  - 0 (Proteins)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (SHC1 protein, human)
RN  - 0 (Shc Signaling Adaptor Proteins)
RN  - 0 (Src Homology 2 Domain-Containing, Transforming Protein 1)
RN  - 0 (Stem Cell Factor)
RN  - 21820-51-9 (Phosphotyrosine)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 3.6.5.2 (HRAS protein, human)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - *Adaptor Proteins, Signal Transducing
MH  - *Adaptor Proteins, Vesicular Transport
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - Aorta/cytology
MH  - Cell Division/drug effects
MH  - Cells, Cultured
MH  - Endothelium, Vascular/drug effects/metabolism
MH  - Enzyme Activation
MH  - *Gene Expression Regulation
MH  - *Genes, fos
MH  - Humans
MH  - Ligands
MH  - MAP Kinase Signaling System/*physiology
MH  - Mitogen-Activated Protein Kinase 1/*metabolism
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Phosphorylation
MH  - Phosphotyrosine/physiology
MH  - *Protein Processing, Post-Translational
MH  - Proteins/*physiology
MH  - Proto-Oncogene Proteins c-kit/*physiology
MH  - Proto-Oncogene Proteins p21(ras)/*metabolism
MH  - Recombinant Fusion Proteins/metabolism/pharmacology
MH  - Shc Signaling Adaptor Proteins
MH  - Src Homology 2 Domain-Containing, Transforming Protein 1
MH  - Stem Cell Factor/pharmacology/physiology
MH  - Swine
MH  - src-Family Kinases/*physiology
EDAT- 1999/10/19 00:00
MHDA- 1999/10/19 00:01
CRDT- 1999/10/19 00:00
PHST- 1999/10/19 00:00 [pubmed]
PHST- 1999/10/19 00:01 [medline]
PHST- 1999/10/19 00:00 [entrez]
AID - 10.1038/sj.onc.1202929 [doi]
PST - ppublish
SO  - Oncogene. 1999 Sep 30;18(40):5546-53. doi: 10.1038/sj.onc.1202929.