Phosphoproteomic Analyses of Interleukin 2 Signaling Reveal Integrated JAK Kinase-Dependent and -Independent Networks in CD8+ T Cells

• Published in: Immunity (Cambridge, Mass.) Mass.), 2016-09, Vol.45 (3), p.685-700
• Main Authors: Ross, Sarah H., Rollings, Christina, Anderson, Karen E., Hawkins, Phillip T., Stephens, Len R., Cantrell, Doreen A.
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Animals; Antigens; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - physiology; Cell Differentiation - physiology; Cell Proliferation - physiology; Cytokines; Cytotoxicity; Experiments; Flow cytometry; GTP Phosphohydrolases - metabolism; Interleukin-2 - metabolism; Janus Kinases - metabolism; Kinases; Lipids; Lymphocytes; Mass spectrometry; Mice; Phosphorylation; Phosphorylation - physiology; Protein-Serine-Threonine Kinases - metabolism; Proteins; Proteome - metabolism; Resource; RNA, Messenger - metabolism; Scholarships & fellowships; Scientific imaging; Signal transduction; Signal Transduction - physiology; Software; Trans-Activators - metabolism
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.07.022

Interleukin-2 (IL-2) is a fundamental cytokine that controls proliferation and differentiation of T cells. Here, we used high-resolution mass spectrometry to generate a comprehensive and detailed map of IL-2 protein phosphorylations in cytotoxic T cells (CTL). The data revealed that Janus kinases (JAKs) couple IL-2 receptors to the coordinated phosphorylation of transcription factors, regulators of chromatin, mRNA translation, GTPases, vesicle trafficking, and the actin and microtubule cytoskeleton. We identified an IL-2-JAK-independent SRC family Tyr-kinase-controlled signaling network that regulates ∼10% of the CTL phosphoproteome, the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), and the activity of the serine/threonine kinase AKT. These data reveal a signaling framework wherein IL-2-JAK-controlled pathways coordinate with IL-2-independent networks of kinase activity and provide a resource toward the further understanding of the networks of protein phosphorylation that program CTL fate. [Display omitted] •Analysis of IL-2-JAK phosphorylation networks in cytotoxic T lymphocytes (CTL)•Over 900 phosphorylations on more than 600 proteins regulated in response to IL-2•SRC family kinases signal in CTLs independently of IL-2 in “pre-organized” networks•Both IL-2-JAK and IL-2-independent signaling regulates pathways that define CTL fate Ross et al. define the interleukin-2 (IL-2)-regulated phosphoproteome of cytotoxic T lymphocytes (CTLs) and reveal that the IL-2-JAK1/3 axis integrates with “pre-organized” phosphorylation networks to drive signaling that determines CTL fate. These data present a resource for further examination of IL-2 signaling pathways.