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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:

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]
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]
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]
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):

CD28+ T cell staining of lymphocytes using human CD28 antibody by Flow cytometric analysis. Lymphocytes were stained with PE-conjugated humanized CD28 antibody and CD19-APC (BD, 555415).

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]. 更多...

CD4 (CD4 Molecule):

TRAT1 - T Cell Receptor Associated Transmembrane Adaptor 1

Western blot analysis of extracts of K-562 cells, using TRAT1 antibody (ABIN5972698).

B2M - beta-2 Microglobulin:

CD247 (CD247 Molecule):

CD3E (CD3e Molecule, epsilon (CD3-TCR Complex)):

CD3G (CD3g Molecule, gamma (CD3-TCR Complex)):

CD3D (CD3d Molecule, delta (CD3-TCR Complex)):

CD8A - CD8:

CD80 (CD80):

CD86 (CD86 Molecule):

CD8B (CD8b Molecule):

HLA-DRA - HLA Class II DR alpha:

HLA-DRB1 (Major Histocompatibility Complex, Class II, DR beta 1):

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

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

HLA-ABC - HLA-ABC:

HLA-ABC 抗体

LAT (Linker For Activation of T Cells):

HLA-A (Major Histocompatibility Complex, Class I, A):

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-DQB1 (Major Histocompatibility Complex, Class II, DQ beta 1):

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

HLA-DRB5 (Major Histocompatibility Complex, Class II, DR beta 5):

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

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

TRAF6 (TNF Receptor-Associated Factor 6):

TMEM189 (Transmembrane Protein 189):

Adaptor Proteins and Regulators

GAB2 (GRB2-Associated Binding Protein 2):

GRAP2 (GRB2-Related Adaptor Protein 2):

GRB2 (Growth Factor Receptor-Bound Protein 2):

LCP2 (Lymphocyte Cytosolic Protein 2 (SH2 Domain Containing Leukocyte Protein of 76kDa)):

MALT1 (Mucosa Associated Lymphoid Tissue Lymphoma Translocation Gene 1):

NCK1 - Cytoplasmic Protein NCK1:

PAG1 (phosphoprotein Associated with Glycosphingolipid Microdomains 1):

PTPN11 (Protein tyrosine Phosphatase, Non-Receptor Type 11):

PTPRC - CD45:

PTPN6 (Protein-tyrosine Phosphatase 1C):

SH3BP2 - SH3-Domain Binding Protein 2:

GEFs and PLCs (Ca2+ regulated)

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

CDC42 (Cell Division Cycle 42 (GTP Binding Protein, 25kDa)):

FLNA - Filamin A:

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

PTEN (Phosphatase and Tensin Homolog):

PTEN 抗体

PIPLC - Phosphoinositide-Specific phospholipase C:

PIPLC ELISA试剂盒

PLC (Phospholipase C):

PLCG1 - Phospholipase C gamma 1:

RAP1A (RAP1A, Member of RAS Oncogene Family):

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)):

STIM1 (Stromal Interaction Molecule 1):

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

VASP (Vasodilator-Stimulated phosphoprotein):

VAV1 (Vav 1 Oncogene):

Kinases

ZAP70 (zeta-Chain (TCR) Associated Protein Kinase 70kDa):

Western Blot: ZAP70 Antibody (3D2A4) [ABIN2587420] - Analysis using ZAP70 mouse mAb against Jurkat cell lysate (1).

PDPK1 (3-phosphoinositide Dependent Protein Kinase-1):

AURKB - Aurora Kinase B:

CSK (C-Src tyrosine Kinase):

CHUK (conserved Helix-Loop-Helix Ubiquitous Kinase):

DRB1 - Dopamine Receptor Binding 1:

DBNL (Drebrin-Like):

FYN (FYN Oncogene Related To SRC, FGR, YES):

FYB (FYN-Binding Protein):

ITK (IL2-Inducible T-Cell Kinase):

INPP5D - Inositol Polyphosphate-5-Phosphatase, 145kDa:

LCK (Lymphocyte-Specific Protein tyrosine Kinase):

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

MAP3K7 (Mitogen-Activated Protein Kinase Kinase Kinase 7):

MAP3K8 (Mitogen-Activated Protein Kinase Kinase Kinase 8):

MAP4K1 (Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1):

PAK1 (P21-Activated Kinase 1):

PAK2 (P21-Activated Kinase 2):

PIK3CA (Phosphoinositide-3-Kinase, Catalytic, alpha Polypeptide):

PI3K p85a - Phosphoinositide 3 Kinase, p85 alpha:

PKC - Protein Kinase C:

PKCa - PKC alpha:

PRKCB - PKC beta:

PRKCE (Protein Kinase C, epsilon):

PRKCQ - PKC theta:

RIPK2 (Receptor-Interacting Serine-threonine Kinase 2):

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

AKT1 - AKT:

Transcription Factors

BCL10 (B-Cell CLL/lymphoma 10):

CARD11 (Caspase Recruitment Domain Family, Member 11):

CCK - Cholecystokinin:

CREBBP - CBP:

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):