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

Författare

Summary, in English

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 (AML). The suppressors of cytokine signaling 6 (SOCS6) is a member of the SOCS family of E3 ubiquitin ligases that can regulate receptor tyrosine kinases signal transduction. In this study we analyzed the role of SOCS6 in Flt3 signal transduction. The results show that ligand stimulation to Flt3 can induce association of SOCS6 and Flt3 and tyrosine phosphorylation of SOCS6. Phospho-peptide fishing indicates that SOCS6 binds directly to phospho-tyrosine 591 and 919 of Flt3. By using stable 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 (ITDs) of Flt3. Taken together, these results suggest that SOCS6 negatively regulates Flt3 activation and downstream Erk signaling pathway and cell proliferation.

Avdelning/ar

Publiceringsår

2012

Språk

Engelska

Sidor

36509-36517

Publikation/Tidskrift/Serie

Journal of Biological Chemistry

Volym

287

Issue

43

Dokumenttyp

Artikel i tidskrift

Förlag

American Society for Biochemistry and Molecular Biology

Ämne

  • Cell and Molecular Biology

Nyckelord

  • ACUTE MYELOID-LEUKEMIA
  • SRC FAMILY KINASES
  • PROTEASOMAL DEGRADATION
  • INSULIN-RECEPTOR
  • C-KIT
  • ACTIVATION
  • PROTEINS
  • DOMAIN
  • AUTOPHOSPHORYLATION
  • PROLIFERATION

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1083-351X