T cell receptor signaling pathway module

The proximal T cell receptor (TCR) signaling pathway, from antigen engagement at the plasma membrane to calcium/NFAT-driven transcription. Peptide-MHC binding by the clonotypic TCR alpha/beta chains is transmitted by the invariant CD3 and CD3 zeta subunits, whose ITAMs are phosphorylated by the Src-family kinase LCK, carried to the complex by the MHC-matched coreceptor (CD4 or CD8) and kept primed by the phosphatase CD45. Doubly phosphorylated ITAMs dock the tandem SH2 domains of ZAP70, which LCK then activates. ZAP70 phosphorylates the transmembrane scaffold LAT and the cytosolic adaptor SLP-76 (LCP2), which the adaptor GADS bridges into the TCR signalosome; the signalosome recruits PLC gamma 1 and the Tec kinase ITK that activates it. PLC gamma 1 hydrolyses PIP2 to IP3 and DAG; IP3-driven calcium entry activates calcineurin, which dephosphorylates NFAT so that it enters the nucleus and activates target genes. The Ras-MAPK/AP-1 and PKC-theta/NF-kappaB branches that also leave the LAT signalosome are outside this module and are modelled in their own modules. Leaf molecular functions follow the ADAPTIVE_IMMUNITY gene reviews of each member.

MODULE:t_cell_receptor_signalingDRAFTSignaling Pathwaymodules/t_cell_receptor_signaling.yaml
T cell receptor signaling pathwayGO:0050852
GO:0050852
T cell receptor signaling pathway
The module is grounded in the GO biological process term for T cell receptor signaling.
gomodel:685de18700002961
T cell receptor signaling (Human).
Production GO-CAM covering the receptor-proximal part of the module (TCR complex, CD4, LCK, CD3E, CD247 and ZAP70 activities). Its activities are linked on the matching annotons below.
file:projects/ADAPTIVE_IMMUNITY.md
Adaptive Immunity project
The member gene reviews (CD3D, CD3E, CD3G, CD247, CD4, CD8A, CD8B, LCK, PTPRC, ZAP70, LAT, LCP2, GRAP2, ITK, PLCG1, PPP3CA, PPP3CB, PPP3R1, NFATC1) are all COMPLETE; each annoton's function is the core molecular function chosen in that gene's review.
8Nodes
5Parts
1Variant Sets
2Variants
13Annotons
4Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:t_cell_receptor_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

10 gene-function check(s) reflected in core functions · 0 conflict(s) · 2 evidence or coverage gap(s) (15 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
tcr_cd3_complex PROTEIN_COMPLEX
Gene 		transmembrane signaling receptor activity
GO:0004888 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
cd4_coreceptor CD4
UniProtKB:P01730
Gene 		coreceptor activity
GO:0015026 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cd8ab_coreceptor PROTEIN_COMPLEX
Gene 		coreceptor activity
GO:0015026 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
lck_kinase LCK
UniProtKB:P06239
Family Representative 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
zap70_kinase ZAP70
UniProtKB:P43403
Family Representative 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cd45_phosphatase PTPRC
UniProtKB:P08575
Gene 		protein tyrosine phosphatase activity
GO:0004725 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
lat_adaptor LAT
UniProtKB:O43561
Gene 		signaling receptor complex adaptor activity
GO:0030159 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slp76_adaptor LCP2
UniProtKB:Q13094
Gene 		signaling adaptor activity
GO:0035591 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gads_adaptor GRAP2
UniProtKB:O75791
Gene 		signaling adaptor activity
GO:0035591 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
itk_kinase ITK
UniProtKB:Q08881
Gene 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
plc_gamma_effector PLCG1
UniProtKB:P19174
Gene 		phosphatidylinositol-4,5-bisphosphate phospholipase C activity
GO:0004435 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
calcineurin_phosphatase PROTEIN_COMPLEX
Gene 		calmodulin-dependent protein phosphatase activity
GO:0033192 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
nfatc1_tf NFATC1
UniProtKB:O95644
Gene 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
lck_kinase LCK Src-family non-receptor tyrosine kinase
PANTHER:PTHR24418:SF39
Family 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24418:SF39.
zap70_kinase ZAP70 Syk-family tyrosine kinase
PANTHER:PTHR24418:SF369
Family 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24418:SF369.

Gene-review completeness (19/19 grounded genes reviewed)

11 complete review(s) · 19 with deep research · 0 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
CD247 P20963 ✓ 125/128 ✓
CD3D P04234 ✓ ✓ ✓
CD3E P07766 ✓ 103/106 ✓
CD3G P09693 ✓ ✓ ✓
CD4 P01730 ✓ 157/162 ✓
CD8A P01732 ✓ ✓ ✓
CD8B P10966 ✓ ✓ ✓
GRAP2 O75791 ✓ ✓ ✓
ITK Q08881 ✓ ✓ ✓
LAT O43561 ✓ ✓ ✓
LCK P06239 ✓ 230/234 ✓
LCP2 Q13094 ✓ 110/111 ✓
NFATC1 O95644 ✓ ✓ ✓
PLCG1 P19174 ✓ 232/233 ✓
PPP3CA Q08209 ✓ 128/131 ✓
PPP3CB P16298 ✓ ✓ ✓
PPP3R1 P63098 ✓ ✓ ✓
PTPRC P08575 ✓ 141/143 ✓
ZAP70 P43403 ✓ ✓ ✓

Details

Context
jawed vertebratesNCBITaxon:7776
plasma membraneGO:0005886 cytosolGO:0005829 nucleusGO:0005634
T cell receptor signaling pathwaySignaling Pathwayt_cell_receptor_signaling
T cell receptor signaling pathwayGO:0050852
Context
jawed vertebratesNCBITaxon:7776
plasma membraneGO:0005886 cytosolGO:0005829 nucleusGO:0005634

Ontology note: GO has no class-neutral peptide-MHC receptor activity term, so the TCR-CD3 complex uses transmembrane signaling receptor activity; the production GO-CAM uses MHC class II receptor activity for the CD4 case. GO also has no cellular component for the CD8 alpha-beta heterodimer.

Connections

TCR-CD3 engagement licenses LCK phosphorylation of ITAMs and ZAP70 recruitment.
Activated ZAP70 phosphorylates LAT and SLP-76, which then assemble the signalosome.
The LAT-SLP-76 signalosome recruits PLC gamma 1 and positions it for activation by ITK.
IP3-driven calcium entry activates calcineurin, which releases NFAT into the nucleus.
Part 1: Antigen recognition and ITAM presentation
TCR-CD3 complex antigen recognitionRegulatory Steptcr_cd3_triggering

The octameric TCR-CD3 complex (TCR alpha/beta with CD3 gamma-epsilon, CD3 delta-epsilon and CD3 zeta-zeta) binds peptide-MHC through the clonotypic alpha/beta chains and transmits that event across the membrane through the ten ITAMs of the invariant CD3 and CD3 zeta chains. The receptor activity belongs to the complex: the CD3 chains contribute adaptor activity and do not bind antigen themselves.

Annotons

TCR-CD3 receptor complex
tcr_cd3_complex
Participant: Protein Complex: alpha-beta T cell receptor complex
Protein Complex:
alpha-beta T cell receptor complexGO:0042105 The clonotypic TCR alpha and beta chains are encoded by rearranged loci and have no single representative UniProt entry; the invariant signaling subunits are listed as active units.
Active units:
CD3D
Participant: Gene Product: CD3D
Gene Product:
CD3DUniProtKB:P04234
Role: ITAM-bearing adaptor subunit (signaling receptor complex adaptor activity) that pairs with CD3E and is needed for complex assembly.
CD3E
Participant: Gene Product: CD3E
Gene Product:
CD3EUniProtKB:P07766
Role: Central ITAM-bearing adaptor subunit of both CD3 dimers; its basic residue-rich sequence recruits LCK and its proline-rich sequence recruits NCK.
CD3G
Participant: Gene Product: CD3G
Gene Product:
CD3GUniProtKB:P09693
Role: ITAM-bearing adaptor subunit that pairs with CD3E and carries the di-leucine motif for TCR internalization.
CD247
Participant: Gene Product: CD247
Gene Product:
CD247UniProtKB:P20963
Role: Disulfide-linked zeta homodimer carrying three tandem ITAMs per chain, the main ZAP70 docking platform.

Function

transmembrane signaling receptor activityGO:0004888

Processes

T cell receptor signaling pathwayGO:0050852

Locations

plasma membraneGO:0005886

Antigen receptor whose phosphorylated ITAMs initiate intracellular signaling.

Variant set: MHC-class-matched coreceptor by T cell lineage (MHC class restriction) (Exactly One)

Conventional alpha-beta T cells use CD4 (MHC class II restricted) or CD8 alpha-beta (MHC class I restricted). The coreceptor binds the same peptide-MHC as the TCR and brings LCK to the complex; it is not a subunit of the TCR complex.

CD4 coreceptor (helper T cells)Regulatory Stepcd4_coreceptor_variant

Annotons

CD4 coreceptor
cd4_coreceptor
Participant: Gene Product: CD4
Gene Product:
CD4UniProtKB:P01730

Function

coreceptor activityGO:0015026

Processes

T cell receptor signaling pathwayGO:0050852

Locations

plasma membraneGO:0005886

Binds MHC class II through its D1 domain and carries LCK on its cytoplasmic tail through a zinc clasp.

CD8 alpha-beta coreceptor (cytotoxic T cells)Regulatory Stepcd8_coreceptor_variant

Annotons

CD8 alpha-beta coreceptor
cd8ab_coreceptor
Participant: Protein Complex: CD8 alpha-beta heterodimer
Protein Complex:
CD8 alpha-beta heterodimer GO has no cellular component term for the CD8 alpha-beta heterodimer.
Active units:
CD8A
Participant: Gene Product: CD8A
Gene Product:
CD8AUniProtKB:P01732
Role: MHC class I binding and the LCK-binding zinc-clasp motif in its cytoplasmic tail.
CD8B
Participant: Gene Product: CD8B
Gene Product:
CD8BUniProtKB:P10966
Role: Contributes to MHC class I binding; its palmitoylated tail partitions CD8 into membrane rafts.

Function

coreceptor activityGO:0015026

Processes

T cell receptor signaling pathwayGO:0050852

Locations

plasma membraneGO:0005886

Binds MHC class I alpha3 and brings LCK to the engaged TCR-CD3 complex.

Part 2: Proximal tyrosine kinase relay
LCK and ZAP70 tyrosine kinase activationReactionlck_zap70_relay

Coreceptor-associated and free LCK phosphorylates the CD3 and CD3 zeta ITAMs. ZAP70 docks on doubly phosphorylated ITAMs through its tandem SH2 domains, is activated by LCK phosphorylation of its interdomain and activation-loop tyrosines, and then phosphorylates LAT and SLP-76. ZAP70 cannot phosphorylate ITAMs itself, so the two kinases act in sequence.

Annotons

LCK Src-family kinase
lck_kinase
Participant: Family: LCK Src-family non-receptor tyrosine kinase
Family:
LCK Src-family non-receptor tyrosine kinasePANTHER:PTHR24418:SF39
Representative Members: LCKUniProtKB:P06239

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

Locations

plasma membraneGO:0005886

Receptor-proximal Src-family kinase that phosphorylates CD3 ITAMs and activates ZAP70.

ZAP70 kinase
zap70_kinase
Participant: Family: ZAP70 Syk-family tyrosine kinase
Family:
ZAP70 Syk-family tyrosine kinasePANTHER:PTHR24418:SF369
Representative Members: ZAP70UniProtKB:P43403

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

Locations

plasma membraneGO:0005886

Syk-family kinase recruited to phospho-ITAMs that phosphorylates LAT and SLP-76.

CD45 receptor tyrosine phosphatase
cd45_phosphatase
Participant: Gene Product: PTPRC
Gene Product:
PTPRCUniProtKB:P08575

Function

protein tyrosine phosphatase activityGO:0004725

Locations

plasma membraneGO:0005886

Removes the inhibitory C-terminal phosphate from LCK (Tyr505), keeping a pool of LCK primed; its large ectodomain excludes it from engaged TCR contacts, and it can also dephosphorylate activating sites and ITAMs.

Part 3: LAT-SLP-76 signalosome assembly
LAT and SLP-76 signalosome assemblyRegulatory Steplat_slp76_signalosome

ZAP70-phosphorylated tyrosines on the palmitoylated transmembrane scaffold LAT dock PLC gamma 1, GRB2 and GADS; GADS bridges LAT to SLP-76, whose own ZAP70-phosphorylated tyrosines recruit VAV1, NCK and ITK. The resulting multivalent assembly forms membrane-associated condensates at the immunological synapse and positions PLC gamma 1 for activation by ITK.

Annotons

LAT transmembrane scaffold
lat_adaptor
Participant: Gene Product: LAT
Gene Product:
LATUniProtKB:O43561

Function

signaling receptor complex adaptor activityGO:0030159

Locations

immunological synapseGO:0001772

Phosphotyrosine scaffold that docks PLC gamma 1, GRB2 and GADS and nucleates TCR signalosome condensates.

SLP-76 cytosolic adaptor
slp76_adaptor
Participant: Gene Product: LCP2
Gene Product:
LCP2UniProtKB:Q13094

Function

signaling adaptor activityGO:0035591

Locations

cytosolGO:0005829

GADS-bound adaptor that recruits VAV1, NCK and ITK to the LAT signalosome, required for PLC gamma 1 activation.

GADS bridging adaptor
gads_adaptor
Participant: Gene Product: GRAP2
Gene Product:
GRAP2UniProtKB:O75791

Function

signaling adaptor activityGO:0035591

Locations

cytosolGO:0005829

SH2 domain binds phospho-LAT and C-terminal SH3 domain binds the SLP-76 RxxK motif, bridging SLP-76 to LAT.

Part 4: Second-messenger generation
PLC gamma 1 PIP2 hydrolysisReactionplcg1_second_messengers

LAT-docked PLC gamma 1, phosphorylated by ITK, hydrolyses phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 releases ER calcium and triggers store-operated calcium entry; DAG feeds the RasGRP/Ras-MAPK and PKC-theta branches modelled elsewhere.

Annotons

ITK Tec-family kinase
itk_kinase
Participant: Gene Product: ITK
Gene Product:
ITKUniProtKB:Q08881

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

Locations

plasma membraneGO:0005886

Recruited to phospho-SLP-76 and activated by LCK; phosphorylates PLC gamma 1 (Tyr783) to switch on PIP2 hydrolysis.

PLC gamma 1
plc_gamma_effector
Participant: Gene Product: PLCG1
Gene Product:
PLCG1UniProtKB:P19174

Function

phosphatidylinositol-4,5-bisphosphate phospholipase C activityGO:0004435

Locations

plasma membraneGO:0005886

Generates IP3 and DAG at the membrane; the same enzyme acts downstream of growth-factor receptor tyrosine kinases in other cell types.

Part 5: Calcium-NFAT transcriptional output
Calcineurin-NFAT transcriptional outputRegulatory Stepnfat_output

Sustained cytosolic calcium activates the phosphatase calcineurin, which dephosphorylates NFAT proteins and exposes their nuclear localization signals. Nuclear NFATC1 binds DNA with AP-1 and other partners to activate target genes such as IL2.

Annotons

Calcineurin
calcineurin_phosphatase
Participant: Protein Complex: calcineurin complex
Protein Complex:
calcineurin complexGO:0005955
Active units:
PPP3CA
Participant: Gene Product: PPP3CA
Gene Product:
PPP3CAUniProtKB:Q08209
Role: Catalytic A subunit (alpha isoform).
PPP3CB
Participant: Gene Product: PPP3CB
Gene Product:
PPP3CBUniProtKB:P16298
Role: Catalytic A subunit (beta isoform); how PPP3CA and PPP3CB divide NFAT dephosphorylation in human T cells is untested.
PPP3R1
Participant: Gene Product: PPP3R1
Gene Product:
PPP3R1UniProtKB:P63098
Role: Ca2+-binding regulatory B subunit required for activity.

Function

calmodulin-dependent protein phosphatase activityGO:0033192

Processes

calcineurin-NFAT signaling cascadeGO:0033173

Locations

cytosolGO:0005829

Ca2+/calmodulin-activated phosphatase that dephosphorylates NFAT and exposes its nuclear localization signals.

NFATC1 transcription factor
nfatc1_tf
Participant: Gene Product: NFATC1
Gene Product:
NFATC1UniProtKB:O95644

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

calcineurin-NFAT signaling cascadeGO:0033173

Locations

nucleusGO:0005634

Calcineurin-activated transcription factor; NFATC2 acts in parallel in T cells and is not modelled separately here.