Advanced

Structural Basis for c-KIT Inhibition by the Suppressor of Cytokine Signaling 6 (SOCS6) Ubiquitin Ligase

Zadjali, F; Pike, AC; Vesterlund, M; Sun, Jianmin LU ; Wu, C; Li, SS; Rönnstrand, Lars LU ; Knapp, Stefan; Bullock, AN and Flores-Morales, Amilcar (2011) In Journal of Biological Chemistry 286(1). p.480-490
Abstract
The c-KIT receptor tyrosine kinase mediates the cellular response to stem cell factor (SCF). Whereas c-KIT activity is important for the proliferation of hematopoietic cells, melanocytes and germ cells, uncontrolled c-KIT activity contributes to the growth of diverse human tumors. Suppressor of cytokine signaling 6 (SOCS6) is a member of the SOCS family of E3 ubiquitin ligases that can interact with c-KIT and suppress c-KIT-dependent pathways. Here, we analyzed the molecular mechanisms that determine SOCS6 substrate recognition. Our results show that the SH2 domain of SOCS6 is essential for its interaction with c-KIT pY568. The 1.45-A crystal structure of SOCS6 SH2 domain bound to the c-KIT substrate peptide (c-KIT residues 564-574)... (More)
The c-KIT receptor tyrosine kinase mediates the cellular response to stem cell factor (SCF). Whereas c-KIT activity is important for the proliferation of hematopoietic cells, melanocytes and germ cells, uncontrolled c-KIT activity contributes to the growth of diverse human tumors. Suppressor of cytokine signaling 6 (SOCS6) is a member of the SOCS family of E3 ubiquitin ligases that can interact with c-KIT and suppress c-KIT-dependent pathways. Here, we analyzed the molecular mechanisms that determine SOCS6 substrate recognition. Our results show that the SH2 domain of SOCS6 is essential for its interaction with c-KIT pY568. The 1.45-A crystal structure of SOCS6 SH2 domain bound to the c-KIT substrate peptide (c-KIT residues 564-574) revealed a highly complementary and specific interface giving rise to a high affinity interaction (K(d) = 0.3 mum). Interestingly, the SH2 binding pocket extends to substrate residue position pY+6 and envelopes the c-KIT phosphopeptide with a large BG loop insertion that contributes significantly to substrate interaction. We demonstrate that SOCS6 has ubiquitin ligase activity toward c-KIT and regulates c-KIT protein turnover in cells. Our data support a role of SOCS6 as a feedback inhibitor of SCF-dependent signaling and provides molecular data to account for target specificity within the SOCS family of ubiquitin ligases. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
286
issue
1
pages
480 - 490
publisher
ASBMB
external identifiers
  • wos:000285782800051
  • scopus:78650938219
ISSN
1083-351X
DOI
10.1074/jbc.M110.173526
language
English
LU publication?
yes
id
e10d0372-de95-479d-80a1-22d57cccc001 (old id 1782238)
date added to LUP
2012-01-19 11:49:05
date last changed
2017-09-24 04:38:00
@article{e10d0372-de95-479d-80a1-22d57cccc001,
  abstract     = {The c-KIT receptor tyrosine kinase mediates the cellular response to stem cell factor (SCF). Whereas c-KIT activity is important for the proliferation of hematopoietic cells, melanocytes and germ cells, uncontrolled c-KIT activity contributes to the growth of diverse human tumors. Suppressor of cytokine signaling 6 (SOCS6) is a member of the SOCS family of E3 ubiquitin ligases that can interact with c-KIT and suppress c-KIT-dependent pathways. Here, we analyzed the molecular mechanisms that determine SOCS6 substrate recognition. Our results show that the SH2 domain of SOCS6 is essential for its interaction with c-KIT pY568. The 1.45-A crystal structure of SOCS6 SH2 domain bound to the c-KIT substrate peptide (c-KIT residues 564-574) revealed a highly complementary and specific interface giving rise to a high affinity interaction (K(d) = 0.3 mum). Interestingly, the SH2 binding pocket extends to substrate residue position pY+6 and envelopes the c-KIT phosphopeptide with a large BG loop insertion that contributes significantly to substrate interaction. We demonstrate that SOCS6 has ubiquitin ligase activity toward c-KIT and regulates c-KIT protein turnover in cells. Our data support a role of SOCS6 as a feedback inhibitor of SCF-dependent signaling and provides molecular data to account for target specificity within the SOCS family of ubiquitin ligases.},
  author       = {Zadjali, F and Pike, AC and Vesterlund, M and Sun, Jianmin and Wu, C and Li, SS and Rönnstrand, Lars and Knapp, Stefan and Bullock, AN and Flores-Morales, Amilcar},
  issn         = {1083-351X},
  language     = {eng},
  number       = {1},
  pages        = {480--490},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Structural Basis for c-KIT Inhibition by the Suppressor of Cytokine Signaling 6 (SOCS6) Ubiquitin Ligase},
  url          = {http://dx.doi.org/10.1074/jbc.M110.173526},
  volume       = {286},
  year         = {2011},
}