Kidins220/ARMS associates with B-Raf and the TCR, promoting sustained Erk signaling in T cells.
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.
Department of Molecular Immunology, Institute of Biology III, Faculty of Biology, University of Freiburg and Max Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Sumit
S
Deswal
Anja
A
Meyer
Gina J
GJ
Fiala
Anja E
AE
Eisenhardt
Lisa C
LC
Schmitt
Mogjiborahman
M
Salek
Tilman
T
Brummer
Oreste
O
Acuto
Wolfgang W A
WW
Schamel
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology; D020690:GTPase-Activating Proteins; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000276:immunology; D061251:Primary Cell Culture; D011485:Protein Binding; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000276:immunology; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology
D001324:Autoantigens; D015415:Biomarkers; D002352:Carrier Proteins; C402110:DOCK2 protein, human; D020690:GTPase-Activating Proteins; C097741:Golgin subfamily A member 2; D020662:Guanine Nucleotide Exchange Factors; C482591:KIDINS220 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011948:Receptors, Antigen, T-Cell; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium