Cytokine-Induced Src Homology 2 Protein (Cis) Promotes T Cell Receptor–Mediated Proliferation and Prolongs Survival of Activated T Cells

Members of the suppressor of cytokine signaling (SOCS) family were discovered as negative regulators of cytokine signaling by inhibition of the Janus kinase–signal transducer and activator of transcription (Jak-STAT) pathway. Among them, cytokine-induced Src homology 2 (SH2) protein (CIS) was found to inhibit the interleukin 3– and erythropietin-mediated STAT5 signaling pathway. However, involvement of SOCS proteins in other signaling pathways is still unknown. This study shows that the expression of CIS is selectively induced in T cells after T cell receptor (TCR) stimulation. In transgenic mice, with selective expression of CIS in CD4 T cells, elevated CIS strongly promotes TCR-mediated proliferation and cytokine production in vitro, and superantigen-induced T cell activation in vivo. Forced expression of CIS also prolongs survival of CD4 T cells after TCR activation. Molecular events immediately downstream from the TCR are not changed in CIS-expressing CD4 T cells, but activation of mitogen-activated protein (MAP) kinase pathways by TCR stimulation is significantly enhanced. Together with the increased MAP kinase activation, a direct interaction of CIS and protein kinase Cθ was also demonstrated. These results suggest that CIS is one of the important regulators of TCR-mediated T cell activation. The functions of CIS, enhancing TCR signaling and inhibiting cytokine signaling, may be important in the regulation of immune response and homeostasis.

• Publication year

  2000

• Venue

  Journal of Experimental Medicine

• Publication date

  2000-03-20

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/JEM.191.6.985PMID 10727460PMCID 2193118
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• SOCS3 is essential in the regulation of fetal liver erythropoiesis.

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• Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells.

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• Adaptors and molecular scaffolds in immune cell signaling.

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• CIS Associates with the Interleukin-2 Receptor β Chain and Inhibits Interleukin-2-dependent Signaling*

  1999cited by this paper
• STAT5 interaction with the T cell receptor complex and stimulation of T cell proliferation.

  1999cited by this paper
• SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine.

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• Integration of T cell receptor-dependent signaling pathways by adapter proteins.

  1999cited by this paper
• Suppression of STAT5 Functions in Liver, Mammary Glands, and T Cells in Cytokine-Inducible SH2-Containing Protein 1 Transgenic Mice

  1999influential reference
• SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality.

  1999cited by this paper
• Adaptors and Molecular Scaffolds in Immune Cell Signaling

  1999influential reference
• Twenty proteins containing a C-terminal SOCS box form five structural classes.

  1998cited by this paper
• Calcineurin preferentially synergizes with PKC‐θ to activate JNK and IL‐2 promoter in T lymphocytes

  1998cited by this paper
• Benign form of congenital angulation of long bones associated with shortening of soft tissues

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• A Sequence of the CIS Gene Promoter Interacts Preferentially with Two Associated STAT5A Dimers: a Distinct Biochemical Difference between STAT5A and STAT5B

  1998cited by this paper
• Mice with a fluorescent marker for interleukin 2 gene activation.

  1998influential reference
• Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice.

  1998cited by this paper
• Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1.

  1998cited by this paper
• Growth Hormone Preferentially Induces the Rapid, Transient Expression of SOCS-3, a Novel Inhibitor of Cytokine Receptor Signaling*

  1998cited by this paper
• Selective modulation of protein kinase C-Θ during T-cell activation

  1997cited by this paper
• Selective modulation of protein kinase C-theta during T-cell activation.

  1997cited by this paper
• A family of cytokine-inducible inhibitors of signalling

  1997cited by this paper
• Structure and function of a new STAT-induced STAT inhibitor

  1997cited by this paper
• SOCS-1/JAB/SSI-1 Can Bind to and Suppress Tec Protein-tyrosine Kinase*

  1997cited by this paper
• A new protein containing an SH2 domain that inhibits JAK kinases

  1997cited by this paper
• CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation.

  1997influential reference
• Cloning and functional characterization of a subunit of the transporter associated with antigen processing.

  1997cited by this paper
• Protein kinase C-theta isoenzyme selective stimulation of the transcription factor complex AP-1 in T lymphocytes

  1996cited by this paper
• T cell antigen receptor signal transduction pathways.

  1996influential reference
• Complex complexes: signaling at the TCR.

  1996cited by this paper
• Mitogen-activated protein kinase cascades and regulation of gene expression.

  1996cited by this paper
• Blocked Signal Transduction to the ERK and JNK Protein Kinases in Anergic CD4+ T Cells

  1996cited by this paper
• A novel cytokine‐inducible gene CIS encodes an SH2‐containing protein that binds to tyrosine‐phosphorylated interleukin 3 and erythropoietin receptors.

  1995influential reference
• Thymic immunopathology and progression of SIVsm infection in cynomolgus monkeys.

  1995cited by this paper
• The Rho family GTPases RhoA, Racl , and CDC42Hsregulate transcriptional activation by SRF

  1995influential reference
• Signal transduction by lymphocyte antigen receptors.

  1994cited by this paper
• T-cell activation by superantigens.

  1994influential reference
• JNK is involved in signal integration during costimulation of T lymphocytes.

  1994influential reference
• A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development.

  1994cited by this paper
• Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain.

  1993cited by this paper
• T cell antigen receptor signal transduction: a tale of tails and cytoplasmic protein-tyrosine kinases.

  1993cited by this paper
• Differential T cell costimulatory requirements in CD28-deficient mice.

  1993cited by this paper
• Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy.

  1992influential reference
• Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction.

  1992cited by this paper

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  2023cites this paper
• Interleukin-15 cytokine checkpoints in natural killer cell anti-tumor immunity.

  2023cites this paper
• METTL14-dependent m6A modification controls iNKT cell development and function

  2022cites this paper
• Impaired energy metabolism and altered functional activity of alveolar type II epithelial cells following exposure of rats to nitrogen mustard.

  2022cites this paper
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  2022cites this paper
• A Randomized Phase II Trial of Idiotype Vaccination and Adoptive Autologous T-Cell Transfer in Multiple Myeloma patients.

  2021cites this paper
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  2021cites this paper
• SOCS Proteins in Immunity, Inflammatory Diseases, and Immune-Related Cancer

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• The function of CISH in T cell differentiation and proliferation

  2020cites this paper
• Negative Regulation of Cytokine Signaling in Immunity.

  2018cites this paper
• Understanding SOCS protein specificity

  2018cites this paper
• Genetic contribution of suppressor of cytokine signalling polymorphisms to the susceptibility to infection after traumatic injury

  2018cites this paper
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  2018cites this paper
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  2018cites this paper
• Natural killer cells and anti-tumor immunity.

  2017cites this paper
• Dissecting the mechanism of severe malaria

  2017cites this paper
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  2017cites this paper
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  2016cites this paper
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  2016cites this paper
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• Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance

  2015cites this paper
• Regulation of Macrophage, Dendritic Cell, and Microglial Phenotype and Function by the SOCS Proteins

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