Suppressor of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3

Julhash U. Kazi, Jianmin Sun, Bengt Phung, Fahad Zadjali, Amilcar Flores-Morales, Lars Rönnstrand

Research output: Contribution to journalArticle

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Abstract

The receptor tyrosine kinase Flt3 is an important growth factor receptor in hematopoiesis, and gain-of-function mutations of the receptor contribute to the transformation of acute myeloid leukemia. SOCS6 (suppressor of cytokine signaling 6) is a member of the SOCS family of E3 ubiquitin ligases that can regulate receptor tyrosine kinase signal transduction. In this study, we analyzed the role of SOCS6 in Flt3 signal transduction. The results show that ligand stimulation of Flt3 can induce association of SOCS6 and Flt3 and tyrosine phosphorylation of SOCS6. Phosphopeptide fishing indicated that SOCS6 binds directly to phosphotyrosines 591 and 919 of Flt3. By using stably transfected Ba/F3 cells with Flt3 and/or SOCS6, we show that the presence of SOCS6 can enhance ubiquitination of Flt3, as well as internalization and degradation of the receptor. The presence of SOCS6 also induces weaker activation of Erk1/2, but not Akt, in transfected Ba/F3 and UT-7 cells and in OCI-AML-5 cells. The absence of SOCS6 promotes Ba/F3 and UT-7 cell proliferation induced by oncogenic internal tandem duplications of Flt3. Taken together, these results suggest that SOCS6 negatively regulates Flt3 activation, the downstream Erk signaling pathway, and cell proliferation.

Original languageEnglish
Pages (from-to)36509-36517
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number43
DOIs
Publication statusPublished - Oct 19 2012

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Signal transduction
Tyrosine
Signal Transduction
Cytokines
Receptor Protein-Tyrosine Kinases
Cell proliferation
Cell Proliferation
Chemical activation
Phosphopeptides
Phosphotyrosine
Ubiquitin-Protein Ligases
Growth Factor Receptors
Ubiquitination
Phosphorylation
Hematopoiesis
Acute Myeloid Leukemia
Association reactions

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Suppressor of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3. / Kazi, Julhash U.; Sun, Jianmin; Phung, Bengt; Zadjali, Fahad; Flores-Morales, Amilcar; Rönnstrand, Lars.

In: Journal of Biological Chemistry, Vol. 287, No. 43, 19.10.2012, p. 36509-36517.

Research output: Contribution to journalArticle

Kazi, Julhash U. ; Sun, Jianmin ; Phung, Bengt ; Zadjali, Fahad ; Flores-Morales, Amilcar ; Rönnstrand, Lars. / Suppressor of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 43. pp. 36509-36517.
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