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Identification of Y589 and Y599 in the juxamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2

Författare

  • Elke Heiss
  • Kristina Masson
  • Christina Sundberg
  • Malin Pedersen
  • Jianmin Sun
  • Susanne Bengtsson
  • Lars Rönnstrand

Summary, in English

Early signal relay steps upon ligand binding to the receptor tyrosine kinase Flt3, i.e. sites of Flt3 autophosphorylation and subsequent docking partners, are mainly unresolved. By immunoprecipitation of specific tryptic peptides contained in the juxtamembrane region

of human Flt3 and subsequent radiosequencing we identified the tyrosine residues 572, 589, 591 and 599 as in vivo autophosphorylation sites. Focusing on Y589 and Y599, we

examined Flt3-ligand-mediated responses in WT-Flt3-, Y589F-Flt3- and Y599F-Flt3-expressing 32D cells. Compared to WT-Flt3-32D cells upon ligand-stimulation, 32DY589F-

Flt3 showed enhanced Erk activation and proliferation/survival whereas 32DY599F-Flt3 cells hereby displayed substantially diminished responses. Both pY589 and pY599 were identified as association sites for signal relay molecules including Src family kinases and SHP2. Consistently, 32D-Y589F-Flt3 and 32D-Y599F-Flt3 showed

decreased FL-triggered activation of Src family kinases. Interference with the Srcdependent negative regulation of Flt3 signaling may account for the enhanced mitogenic

response of Y589F-Flt3. Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation dependent manner. As Y599F-Flt3-32D

was unable to associate with and to phosporylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3-phenotype we hypothesize that

recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation.

Publiceringsår

2006

Språk

Engelska

Sidor

1542-1550

Publikation/Tidskrift/Serie

Blood

Volym

108

Issue

5

Dokumenttyp

Artikel i tidskrift

Förlag

American Society of Hematology

Ämne

  • Hematology

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1528-0020