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

37 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

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Ligases
Ubiquitin
Cytokines
Stem Cell Factor
src Homology Domains
Substrates
Phosphopeptides
Ubiquitin-Protein Ligases
Melanocytes
Receptor Protein-Tyrosine Kinases
Germ Cells
Inhibition (Psychology)
Tumors
Cell Proliferation
Crystal structure
Cells
Peptides
Feedback
Growth
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Structural basis for c-KIT inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase. / Zadjali, Fahad; Pike, Ashley C W; Vesterlund, Mattias; Sun, Jianmin; Wu, Chenggang; Li, Shawn S C; Rönnstrand, Lars; Knapp, Stefan; Bullock, Alex N.; Flores-Morales, Amilcar.

In: Journal of Biological Chemistry, Vol. 286, No. 1, 07.01.2011, p. 480-490.

Research output: Contribution to journalArticle

Zadjali, F, Pike, ACW, Vesterlund, M, Sun, J, Wu, C, Li, SSC, Rönnstrand, L, Knapp, S, Bullock, AN & Flores-Morales, A 2011, 'Structural basis for c-KIT inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase', Journal of Biological Chemistry, vol. 286, no. 1, pp. 480-490. https://doi.org/10.1074/jbc.M110.173526
Zadjali, Fahad ; Pike, Ashley C W ; Vesterlund, Mattias ; Sun, Jianmin ; Wu, Chenggang ; Li, Shawn S C ; Rönnstrand, Lars ; Knapp, Stefan ; Bullock, Alex N. ; Flores-Morales, Amilcar. / Structural basis for c-KIT inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 1. pp. 480-490.
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