The autoimmunity risk variant LYP-W620 cooperates with CSK in the regulation of TCR signaling

PLoS One. 2013;8(1):e54569. doi: 10.1371/journal.pone.0054569. Epub 2013 Jan 24.

Abstract

The protein tyrosine phosphatase LYP, a key regulator of TCR signaling, presents a single nucleotide polymorphism, C1858T, associated with several autoimmune diseases such as type I diabetes, rheumatoid arthritis, and lupus. This polymorphism changes an R by a W in the P1 Pro rich motif of LYP, which binds to CSK SH3 domain, another negative regulator of TCR signaling. Based on the analysis of the mouse homologue, Pep, it was proposed that LYP and CSK bind constitutively to inhibit LCK and subsequently TCR signaling. The detailed study of LYP/CSK interaction, here presented, showed that LYP/CSK interaction was inducible upon TCR stimulation, and involved LYP P1 and P2 motifs, and CSK SH3 and SH2 domains. Abrogating LYP/CSK interaction did not preclude the regulation of TCR signaling by these proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmune Diseases / genetics
  • Autoimmunity*
  • CSK Tyrosine-Protein Kinase
  • Electrophoresis, Polyacrylamide Gel
  • Flow Cytometry
  • HEK293 Cells
  • Humans
  • Immunohistochemistry
  • Jurkat Cells
  • Models, Molecular
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • Protein Binding
  • Protein Tyrosine Phosphatases / genetics*
  • Protein Tyrosine Phosphatases / physiology
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction / physiology*
  • src-Family Kinases / physiology*

Substances

  • Receptors, Antigen, T-Cell
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • Protein Tyrosine Phosphatases

Grant support

This work was supported by a grant (SAF2009-09724) from Ministerio de Ciencia e Innovación (MICINN,http://www.idi.mineco.gob.es/portal/site/MICINN), by Fundación Mutua Madrileña (http://www.fundacionmutua.es), and by Red Cardiovascular (RECAVA) from Instituto de Salud Carlos III (http://www.recava.com). Y. Bayón has been under contract within the Ramón y Cajal Program of the Ministerio de Educación y Ciencia of Spain, co-funded by the European Social Fund through FEDER-FSE (http://www.educacion.gob.es). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.