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The activation kinetics of MAPK Erk are critical for T cell development and activation. In particular, sustained Erk signaling is required for T cell activation and effector functions, such as IL-2 production. Although Raf-1 triggers transient Erk activation, B-Raf is implicated in sustained Erk signaling after TCR stimulation. In this study, we show that B-Raf is dephosphorylated on its inhibitory serine 365 upon TCR triggering. However, it is unknown how B-Raf activation is coupled to the TCR. Using mass spectrometry, we identified protein kinase D-interacting substrate of 220 kDa (Kidins220)/ankyrin repeat-rich membrane spanning protein, mammalian target of rapamycin, Rictor, Dock2, and GM130 as novel B-Raf interaction partners. We focused on Kidins220, a protein that has been studied in neuronal cells and found that it associated with the pre-TCR, αβTCR, and γδTCR. Upon prolonged TCR stimulation, the Kidins220-TCR interaction was reduced, as demonstrated by immunoprecipitation and proximity ligation assays. We show that Kidins220 is required for TCR-induced sustained, but not transient, Erk activation. Consequently, induction of the immediate early gene products and transcription factors c-Fos and Erg-1 was blocked, and upregulation of the activation markers CD69, IL-2, and IFN-γ was reduced. Further, Kidins220 was required for optimal calcium signaling. In conclusion, we describe Kidins220 as a novel TCR-interacting protein that couples B-Raf to the TCR. Kidins220 is mandatory for sustained Erk signaling; thus, it is crucial for TCR-mediated T cell activation.

Original publication

DOI

10.4049/jimmunol.1200653

Type

Journal article

Journal

J Immunol

Publication Date

01/03/2013

Volume

190

Pages

1927 - 1935

Keywords

Animals, Autoantigens, Biomarkers, Calcium, Carrier Proteins, Cell Line, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Guanine Nucleotide Exchange Factors, Humans, Lymphocyte Activation, Membrane Proteins, Mice, Nerve Tissue Proteins, Primary Cell Culture, Protein Binding, Proto-Oncogene Proteins B-raf, Rapamycin-Insensitive Companion of mTOR Protein, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, TOR Serine-Threonine Kinases