期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 1, 页码 480-490出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.173526
关键词
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资金
- Novo Nordisk Foundation Center for Protein Research
- Swedish Research Council
- Cancer-fonden
- Sultan Qaboos University
- Swedish Cancer Society
- Swedish Childrens Cancer Society
- Gunnar Nilsson Cancer Society
- Alfred Osterlund Foundation
- Skane University Hospital
- Skane University Hospital Cancer Foundation
- Canadian Cancer Society
- Canadian Institutes for Health Research [1097737]
- Canadian Foundation for Innovation
- Genome Canada through the Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck Co., Inc
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
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-angstrom 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 mu M). 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.
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