Advanced

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

Kazi, Julhash U. LU ; Sun, Jianmin LU ; Phung, Bengt LU ; Zadjali, Fahad; Flores-Morales, Amilcar and Rönnstrand, Lars LU (2012) In Journal of Biological Chemistry 287(43). p.36509-36517
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 (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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ACUTE MYELOID-LEUKEMIA, SRC FAMILY KINASES, PROTEASOMAL DEGRADATION, INSULIN-RECEPTOR, C-KIT, ACTIVATION, PROTEINS, DOMAIN, AUTOPHOSPHORYLATION, PROLIFERATION
in
Journal of Biological Chemistry
volume
287
issue
43
pages
36509 - 36517
publisher
ASBMB
external identifiers
  • wos:000310364000070
  • pmid:22952242
  • scopus:84867778695
ISSN
1083-351X
DOI
10.1074/jbc.M112.376111
language
English
LU publication?
yes
id
f09a8233-5722-4601-b55b-3cb3c7417f35 (old id 3124260)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22952242?dopt=Abstract
date added to LUP
2012-10-04 15:17:29
date last changed
2017-11-05 03:09:28
@article{f09a8233-5722-4601-b55b-3cb3c7417f35,
  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 (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.},
  author       = {Kazi, Julhash U. and Sun, Jianmin and Phung, Bengt and Zadjali, Fahad and Flores-Morales, Amilcar and Rönnstrand, Lars},
  issn         = {1083-351X},
  keyword      = {ACUTE MYELOID-LEUKEMIA,SRC FAMILY KINASES,PROTEASOMAL DEGRADATION,INSULIN-RECEPTOR,C-KIT,ACTIVATION,PROTEINS,DOMAIN,AUTOPHOSPHORYLATION,PROLIFERATION},
  language     = {eng},
  number       = {43},
  pages        = {36509--36517},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Suppressor Of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated Tyr 591 and Tyr 919 of Flt3.},
  url          = {http://dx.doi.org/10.1074/jbc.M112.376111},
  volume       = {287},
  year         = {2012},
}