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SOCS2 Binds to and Regulates EphA2 through Multiple Mechanisms

Carissa Pilling1,2, Jonathan A Cooper3

  • 1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, Washington, 98109, USA.

Scientific Reports
|September 9, 2017
PubMed

Insights

Suppressors of cytokine signaling (SOCS) proteins regulate cell signaling. This study reveals SOCS2 interacts with EphA2, influencing its levels and epithelial cell transformation, through both direct and indirect mechanisms.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Suppressors of cytokine signaling (SOCS) proteins are key regulators of cellular signaling pathways.
  • SOCS proteins function through Cullin5-RING E3 ubiquitin ligase (CRL5)-dependent and -independent mechanisms.
  • CRL5, SOCS2, and SOCS6 are involved in suppressing epithelial cell transformation.

Purpose of the Study:

  • To identify proteins interacting with SOCS2 and SOCS6 using proteomics.
  • To investigate the interaction between SOCS2 and the receptor tyrosine kinase EphA2.
  • To elucidate the mechanisms by which SOCS2 influences EphA2 levels and cellular transformation.

Main Methods:

  • Utilized BioID and Flag affinity purification mass spectrometry to identify protein interactors of SOCS2 and SOCS6.
  • Investigated the binding requirements between SOCS2 and EphA2, including the role of the SOCS2 SH2 domain and EphA2 autophosphorylation.
  • Analyzed the effect of SOCS2 overexpression on EphA2 steady-state levels and EphA1 expression.

Main Results:

  • Identified Ephrin type-A receptor 2 (EphA2) as a SOCS2-interacting protein.
  • SOCS2-EphA2 binding occurs in endosomes and requires SOCS2 SH2 domain and EphA2 activation loop autophosphorylation.
  • SOCS2 overexpression indirectly decreases EphA2 levels by inducing Ephrin A1 (EfnA1) expression, which then down-regulates EphA2.

Conclusions:

  • SOCS2 interacts with EphA2, a receptor tyrosine kinase, within endosomes.
  • SOCS2 overexpression can lead to indirect down-regulation of EphA2 via EfnA1 induction.
  • SOCS proteins may regulate receptor tyrosine kinases through both direct and indirect mechanisms, impacting epithelial cell transformation.

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