Kidins220/ARMS associates with B-Raf and the TCR, promoting sustained Erk signaling in T cells

• Published in: The Journal of immunology (1950) 2013-03, Vol.190 (5), p.1927-1935
• Main Authors: Deswal, Sumit, Meyer, Anja, Fiala, Gina J, Eisenhardt, Anja E, Schmitt, Lisa C, Salek, Mogjiborahman, Brummer, Tilman, Acuto, Oreste, Schamel, Wolfgang W A
• Format: Article
• Language: English
• Subjects: Animals; Autoantigens - genetics; Autoantigens - immunology; Biomarkers - metabolism; Calcium - metabolism; Carrier Proteins - genetics; Carrier Proteins - immunology; Cell Line; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - immunology; Gene Expression Regulation; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - immunology; Humans; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - immunology; Primary Cell Culture; Protein Binding; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - immunology; Rapamycin-Insensitive Companion of mTOR Protein; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Signal Transduction - genetics; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1200653

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.