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:
https://lup.lub.lu.se/record/3124260
- author
- Kazi, Julhash U.
LU
; Sun, Jianmin
LU
; Phung, Bengt
LU
; Zadjali, Fahad
; Flores-Morales, Amilcar
and Rönnstrand, Lars
LU
- organization
- publishing date
- 2012
- 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
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000310364000070
- pmid:22952242
- scopus:84867778695
- pmid:22952242
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M112.376111
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)
- 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
- 2016-04-01 10:17:34
- date last changed
- 2022-03-27 06:53:24
@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}},
keywords = {{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 = {{American Society for Biochemistry and Molecular Biology}},
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 = {{https://lup.lub.lu.se/search/files/1721108/3631887.pdf}},
doi = {{10.1074/jbc.M112.376111}},
volume = {{287}},
year = {{2012}},
}