Structural basis for c-KIT inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase.
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.
Mesh Terms:
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
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
J. Biol. Chem.
Date: Jan. 07, 2011
PubMed ID: 21030588
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