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TCR Signaling

The T-Cell Receptor is a protein complex on the surface of T-cell responsible for antigen recognition. The activation induces a number of signaling cascades finally leading to the transcription of several gene products which allow the T cells to differentiate, proliferate and secrete a number of cytokines.

Src-family kinases (SFKs1 ) Lck and Fyn phosphorylate TCR ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3, creating a docking site for ZAP-70. Phosphorylation and activation is modulated by CD45 receptor2 . Zap-70 binds to CD3 zeta chain which positions the protein kinase to phosphorylate the transmembrane protein linker of activated T cells (LAT).

Signaling proteins like SLP-76 can now dock to LAT and gets phosporylated by ZAP-70 as well3. SLP-76 promotes recruitment of Vav (GEF), the adaptor proteins NCK and GADS, and an inducible T cell kinase (Itk). Ltk enables PLCγ1 by phosphorylation which leads to hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the second messengers diacylglycerol (DAG) and inositol trisphosphate (IP3).

Phosphorylation of phospholipase C γ1 (PLCγ1) by Itk results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the second messenger inositol trisphosphate (IP3) and DAG. DAG activates PKC4 and the MAPK/Erk pathways cascade which leads to activation of transcription factor NF-κB and ATF2 activation and relocation into nucleolus. IP3 promotes release of Ca2+ from the ER, which triggers entry of extracellular Ca2+ into cells through calcium release-activated Ca2+ (CRAC) channels. Calcium-bound calmodulin (Ca2+/CaM) activates the phosphatase calcineurin. Transcription factor NFAT gets activated and promotes IL-2 gene transcription.

The signal cascades are regulated on several occasions to diversify the cell answer. Extracellular signals are recognized by additional cell surface receptors like CD28 or LFA-1 and further regulate cellular response.


References:

  1. Braiman, A and Isakov, N (2015): "The Role of Crk Adaptor Proteins in T-Cell Adhesion and Migration”. Front. Immunol., v.6,2015. [PMID: 4593252]
  2. Courtney, AH (2017): “A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45. ”. Mol Cell , 3;67(3):498-511 [PMID: 28735895]
  3. Wang HY (2001): “Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70.” J Biol Chem, 276(28):26004-11. [PMID: 11353765]
  4. Lio Y (1999): “Protein kinase C activation inhibits tyrosine phosphorylation of Cbl and its recruitment of Src homology 2 domain-containing proteins.” J Immunol, 162(12):7095-101 [PMID: 10358153]


Receptor and Membrane Proteins

CD28 (CD28):

The protein encoded by this gene is essential for T-cell proliferation and survival, cytokine production, and T-helper type-2 development. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011].   More...

HLA-DRB3 (Major Histocompatibility Complex, Class II, DR beta 3):

HLA-DRB4 - Major Histocompatibility Complex, Class II, DR beta 4:

HLA-DPA1 - Major Histocompatibility Complex, Class II, DP alpha 1:

HLA-DPB1 (Major Histocompatibility Complex, Class II, DP beta 1):

HLA-DQA1 - Major Histocompatibility Complex, Class II, DQ alpha 1:

HLA-DQA2 - Major Histocompatibility Complex, Class II, DQ alpha 2:

HLA-DQB2 (Major Histocompatibility Complex, Class II, DQ beta 2):

SHC1 (SHC (Src Homology 2 Domain Containing) Transforming Protein 1):

SLC25A20 - Solute Carrier Family 25 (Carnitine/acylcarnitine Translocase), Member 20:

Adaptor Proteins and Regulators

GEFs and PLCs (Ca2+ regulated)

CBL (Cas-Br-M (Murine) Ecotropic Retroviral Transforming Sequence):

ORAI1 (ORAI Calcium Release-Activated Calcium Modulator 1):

PTEN (Phosphatase and Tensin Homolog):

PIPLC - Phosphoinositide-Specific phospholipase C:

RASSF5 (Ras Association (RalGDS/AF-6) Domain Family Member 5):

RASGRP1 - RAS Guanyl Releasing Protein 1 (Calcium and DAG-Regulated):

RASGRP2 (RAS Guanyl Releasing Protein 2 (Calcium and DAG-Regulated)):

SOS1 (Son of Sevenless Homolog 1 (Drosophila)):

TRPV6 (Transient Receptor Potential Cation Channel, Subfamily V, Member 6):

Kinases

DRB1 - Dopamine Receptor Binding 1:

MAP3K14 (Mitogen-Activated Protein Kinase Kinase Kinase 14):

PKC - Protein Kinase C:

TAB2 (TGF-beta Activated Kinase 1/MAP3K7 Binding Protein 2):

Transcription Factors

CARD11 (Caspase Recruitment Domain Family, Member 11):

IKBKB (Inhibitor of kappa Light Polypeptide Gene Enhancer in B-Cells, Kinase beta):

IKBKG (Inhibitor of kappa Light Polypeptide Gene Enhancer in B-Cells, Kinase gamma):

NFKB1 (Nuclear Factor of kappa Light Polypeptide Gene Enhancer in B-Cells 1):

NFKBIA (Nuclear Factor of kappa Light Polypeptide Gene Enhancer in B-Cells Inhibitor, alpha):

RIP2 (ROP Interactive Partner 2):

UBE2V1 (Ubiquitin-Conjugating Enzyme E2 Variant 1):

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