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

F Zadjali, AC Pike, M Vesterlund, Jianmin Sun, C Wu, SS Li, Lars Rönnstrand, Stefan Knapp, AN Bullock, Amilcar Flores-Morales

Research output: Contribution to journalArticlepeer-review

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

Bibliographical note

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)

Subject classification (UKÄ)

  • Medicinal Chemistry

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