Structural basis for c-KIT inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase

Fahad Zadjali, Ashley C W Pike, Mattias Vesterlund, Jianmin Sun, Chenggang Wu, Shawn S C Li, Lars Rönnstrand, Stefan Knapp, Alex N. Bullock, Amilcar Flores-Morales

Research output: Contribution to journalArticle

40 Citations (Scopus)

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-Å 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 (Kd = 0.3 μM). 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.

Original languageEnglish
Pages (from-to)480-490
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number1
DOIs
Publication statusPublished - Jan 7 2011

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Zadjali, F., Pike, A. C. W., Vesterlund, M., Sun, J., Wu, C., Li, S. S. C., Rönnstrand, L., Knapp, S., Bullock, A. N., & Flores-Morales, A. (2011). Structural basis for c-KIT inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase. Journal of Biological Chemistry, 286(1), 480-490. https://doi.org/10.1074/jbc.M110.173526