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

Research output: Contribution to journalJournal articleResearchpeer-review

  • 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
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 (K(d) = 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
JournalJournal of Biological Chemistry
Volume286
Issue number1
Pages (from-to)480-90
Number of pages11
ISSN0021-9258
DOIs
Publication statusPublished - 2011

    Research areas

  • Amino Acid Sequence, HEK293 Cells, Humans, Models, Molecular, Molecular Sequence Data, Phosphopeptides, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Proto-Oncogene Proteins c-kit, Signal Transduction, Stem Cell Factor, Substrate Specificity, Suppressor of Cytokine Signaling Proteins, Ubiquitination, src Homology Domains

ID: 40297799