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

María Luisa de la Puerta; Antonio G Trinidad; María del Carmen Rodríguez; José María de Pereda; Mariano Sánchez Crespo; Yolanda Bayón; Andrés Alonso

doi:10.1371/journal.pone.0054569

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.

Authors

María Luisa de la Puerta¹, Antonio G Trinidad, María del Carmen Rodríguez, José María de Pereda, Mariano Sánchez Crespo, Yolanda Bayón, Andrés Alonso

Affiliation

¹ Instituto de Biología y Genética Molecular (IBGM), CSIC-Universidad de Valladolid, Valladolid, Spain.

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

Grants and funding

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.