scholarly journals CD3/CD28 Costimulation-Induced NF-κB Activation Is Mediated by Recruitment of Protein Kinase C-θ, Bcl10, and IκB Kinase β to the Immunological Synapse through CARMA1

2004 ◽  
Vol 24 (1) ◽  
pp. 164-171 ◽  
Author(s):  
Donghai Wang ◽  
Reiko Matsumoto ◽  
Yun You ◽  
Tuanjie Che ◽  
Xue-Yan Lin ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Lipid Rafts ◽  
Immunological Synapse ◽  
Membrane Association ◽  
Downstream Signaling ◽  
Kinase C ◽  
Iκb Kinase ◽  
Cd28 Costimulation

ABSTRACT CARMA1 (also known as CARD11) is a scaffold molecule and contains a caspase-recruitment domain (CARD) and a membrane-associated guanylate kinase-like (MAGUK) domain. It plays an essential role in mediating CD3/CD28 costimulation-induced NF-κB activation. However, the molecular mechanism by which CARMA1 mediates costimulatory signals remains to be determined. Here, we show that CARMA1 is constitutively associated with the cytoplasmic membrane. This membrane association is essential for the function of CARMA1, since a mutant of CARMA1, CARMA1(L808P), that is defective in the membrane association cannot rescue CD3/CD28 costimulation-induced NF-κB activation in JPM50.6 CARMA1-deficient T cells. Although CD3/CD28 costimulation effectively induces the formation of the immunological synapse in CARMA1-deficient T cells, the recruitment of protein kinase C-θ (PKC-θ), Bcl10, and IκB kinase β (IKKβ) into lipid rafts of the immunological synapse is defective. Moreover, expression of wild-type CARMA1, but not CARMA1(L808P), restores the recruitment of PKC-θ, Bcl10, and IKKβ into lipid rafts in CARMA1-deficient T cells. Consistently, expression of a mutant CARMA1, CARMA1(ΔCD), that cannot associate with Bcl10 failed to restore CD3/CD28 costimulation-induced NF-κB activation in JPM50.6 cells, whereas expression of Bcl10-CARMA(ΔCD) fusion protein effectively restored this NF-κB activation. Together, these results indicate that CARMA1 mediates CD3/CD28 costimulation-induced NF-κB activation by recruiting downstream signaling components into the immunological synapse.

scholarly journals Protein Kinase C-θ Participates in NF-κB Activation Induced by CD3-CD28 Costimulation through Selective Activation of IκB Kinase β

2000 ◽  
Vol 20 (8) ◽  
pp. 2933-2940 ◽  
Author(s):  
Xin Lin ◽  
Alison O'Mahony ◽  
Yajun Mu ◽  
Romas Geleziunas ◽  
Warner C. Greene
Keyword(s):  
T Cells ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Jurkat T Cells ◽  
Necrosis Factor Alpha ◽  
Kinase C ◽  
Iκb Kinase ◽  
Cd28 Costimulation

ABSTRACT The NF-κB/Rel family of eukaryotic transcription factors plays an essential role in the regulation of inflammatory, antiapoptotic, and immune responses. NF-κB is activated by many stimuli including costimulation of T cells with ligands specific for the T-cell receptor (TCR)-CD3 complex and CD28 receptors. However, the signaling intermediates that transduce these costimulatory signals from the TCR-CD3 and CD28 surface receptors leading to nuclear NF-κB expression are not well defined. We now show that protein kinase C-θ (PKC-θ), a novel PKC isoform, plays a central role in a signaling pathway induced by CD3-CD28 costimulation leading to activation of NF-κB in Jurkat T cells. We find that expression of a constitutively active mutant of PKC-θ potently induces NF-κB activation and stimulates the RE/AP composite enhancer from the interleukin-2 gene. Conversely, expression of a kinase-deficient mutant or antisense PKC-θ selectively inhibits CD3-CD28 costimulation, but not tumor necrosis factor alpha-induced activation of NF-κB in Jurkat T cells. The induction of NF-κB by PKC-θ is mediated through the activation of IκB kinase β (IKKβ) in the absence of detectable IKKα stimulation. PKC-θ acts directly or indirectly to stimulate phosphorylation of IKKβ, leading to activation of this enzyme. Together, these results implicate PKC-θ in one pathway of CD3-CD28 costimulation leading to NF-κB activation that is apparently distinct from that involving Cot and NF-κB-inducing kinase (NIK). PKC-θ activation of NF-κB is mediated through the selective induction of IKKβ, while the Cot- and NIK-dependent pathway involves induction of both IKKα and IKKβ.

scholarly journals Protein Kinase C δ Regulates the Depletion of Actin at the Immunological Synapse Required for Polarized Exosome Secretion by T Cells

2019 ◽  
Vol 10 ◽  
Author(s):  
Gonzalo Herranz ◽  
Pablo Aguilera ◽  
Sergio Dávila ◽  
Alicia Sánchez ◽  
Bianca Stancu ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Immunological Synapse ◽  
Kinase C

scholarly journals Protein Kinase C-Theta (PKCθ): A Rheostat in T cell Signaling and Cancer

2016 ◽  
Vol 1 (2) ◽  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
Protein Kinase C ◽  
T Cell ◽  
Protein Kinase ◽  
Cell Signaling ◽  
Immunological Synapse ◽  
Signal Transduction Pathway ◽  
T Cell Signaling ◽  
Kinase C

Protein kinase C-theta (PKCθ) is a key enzyme in T lymphocytes signal transduction pathway that works downstream of the activated T cell receptor (TCR) and the CD28 receptor. This protein translocates to the center of the immunological synapse (IS) as T cells encounter an antigen. Depending on the quality and quantity of extracellular antigenic stimuli, PKCθ differentially phosphorylates and activates different effector molecules that mediate signal transduction into distinct subcellular compartments and activate the major T cell responsive transcription factors, NF-κB, NFAT and AP-1. Besides having a major biological role in T cells, PKCθ is also expressed at high levels in gastrointestinal stromal tumors, although the functional importance is not fully clear. The present manuscript shades light on the current understanding on PKCθ in T cell signaling and cancer.

scholarly journals Protein Kinase C θ Affects Ca2+ Mobilization and NFAT Activation in Primary Mouse T Cells

2003 ◽  
Vol 197 (11) ◽  
pp. 1525-1535 ◽  
Author(s):  
Christa Pfeifhofer ◽  
Kurt Kofler ◽  
Thomas Gruber ◽  
Nassim Ghaffari Tabrizi ◽  
Christina Lutz ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase C ◽  
T Cell ◽  
Protein Kinase ◽  
Immunological Synapse ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Kinase C ◽  
Primary Mouse ◽  
Nfat Activation

Protein kinase C (PKC)θ is an established component of the immunological synapse and has been implicated in the control of AP-1 and NF-κB. To study the physiological function of PKCθ, we used gene targeting to generate a PKCθ null allele in mice. Consistently, interleukin 2 production and T cell proliferative responses were strongly reduced in PKCθ-deficient T cells. Surprisingly, however, we demonstrate that after CD3/CD28 engagement, deficiency of PKCθ primarily abrogates NFAT transactivation. In contrast, NF-κB activation was only partially reduced. This NFAT transactivation defect appears to be secondary to reduced inositol 1,4,5-trisphosphate generation and intracellular Ca2+ mobilization. Our finding suggests that PKCθ plays a critical and nonredundant role in T cell receptor–induced NFAT activation.

Sign in / Sign up

Export Citation Format

Share Document