SCIMP-scaffolded TLR tyrosine phosphorylation module

A non-TIR adaptor branch of Toll-like receptor signalling in macrophages. After LPS activates TLR4 (see modules/tlr4_md2_lps_signaling.yaml), the palmitoylated transmembrane adaptor SCIMP binds the TLR4 TIR domain. SCIMP carries the Src-family kinase LYN constitutively on its proline-rich region and, once its tyrosines are phosphorylated, recruits SYK through both SYK SH2 domains. LYN and SYK phosphorylate TLR4 on its TIR domain (mouse Y672, human Y674), and SCIMP recruits ERK1/2 to TLR4 in membrane ruffles, leading to c-FOS activation and a selective IL-6 and IL-12p40 response. CSK, docking on a separate SCIMP phosphotyrosine, provides negative feedback. The branch runs alongside the TIRAP-MYD88 and TRAM-TRIF branches and does not replace them.

MODULE:scimp_tlr_tyrosine_kinase_scaffoldDRAFTABSTRACTSignaling Pathwaymodules/scimp_tlr_tyrosine_kinase_scaffold.yaml

toll-like receptor 4 signaling pathwayGO:0034142

PMID:28098138

SCIMP is a non-TIR adaptor that binds the TLR4 TIR domain after LPS stimulation.

SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide.

Evidence is mostly from mouse macrophages (bone-marrow-derived and RAW264.7); human support is a THP-1 experiment (PMID:35337798) and the conserved human TLR4 Y674 (PMID:37058370). Human gene products are used as members for consistency with tlr4_md2_lps_signaling. SCIMP is immune-restricted, so the branch is specific to antigen-presenting cells. GRB2 and SLP65 (BLNK) also dock on phospho-SCIMP after LPS, but what they contribute to TLR output is unknown, so they are not modelled as parts. No production GO-CAM includes SCIMP. The same scaffold acts downstream of TLR1/2, TLR3 and TLR7 and of Dectin-1, but receptor binding and kinase recruitment have only been shown for TLR4 (and TLR2 binding), so TLR4 is the modelled receptor.

6Nodes

5Parts

0Variant Sets

0Variants

7Annotons

6Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

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

Leaf nodes lacking representative members

✓ representative grounding skipped for abstract module.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

7 gene-function check(s) reflected in core functions · 0 conflict(s) · 0 evidence or coverage gap(s) (7 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.

Annoton	Participant	Function	Assessment
scimp_branch_tlr4	TLR4 UniProtKB:O00206 Gene	signaling receptor activity GO:0038023	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scimp_adaptor	SCIMP UniProtKB:Q6UWF3 Gene	signaling adaptor activity GO:0035591	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scimp_branch_lyn	LYN UniProtKB:P07948 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).
scimp_branch_syk	SYK UniProtKB:P43405 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).
scimp_branch_mapk1	MAPK1 UniProtKB:P28482 Gene	MAP kinase activity GO:0004707	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scimp_branch_mapk3	MAPK3 UniProtKB:P27361 Gene	MAP kinase activity GO:0004707	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scimp_branch_csk	CSK UniProtKB:P41240 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).

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

scimp_csk_feedback ⊣ scimp_tyrosine_kinase_relay [closed]
scimp_csk_feedback is regulated by scimp_scaffold: feedback loop closed

Gene-review completeness (7/8 grounded genes reviewed)

3 complete review(s) · 4 with deep research · 1 missing review · 3 reviewed but lacking deep research

Gene	Review	Complete	Deep research
CSK P41240	✓	✓	✗
LYN P07948	✓	316/320	✓
MAPK1 P28482	✓	✓	✓
MAPK3 P27361	✓	244/247	✓
FOS P01100	✗	—	—
SCIMP Q6UWF3	✓	✓	✗
SYK P43405	✓	264/278	✗
TLR4 O00206	✓	274/275	✓

Tree

SCIMP TLR tyrosine-kinase scaffoldSignaling Pathwayscimp_tlr_tyrosine_kinase_scaffold

Parts
1. 1. activated receptor
2. LPS-activated TLR4Regulatory Stepscimp_tlr4_receptor
  
  Annotons
  - TLR4 signaling receptor Gene Product: TLR4
3. 2. transmembrane scaffold
4. SCIMP transmembrane scaffoldRegulatory Stepscimp_scaffold
  
  Annotons
  - SCIMP signaling adaptor Gene Product: SCIMP
5. 3. receptor tyrosine phosphorylation
6. LYN and SYK tyrosine kinasesRegulatory Stepscimp_tyrosine_kinase_relay
  
  Annotons
  - LYN tyrosine kinase Gene Product: LYN
  - SYK tyrosine kinase Gene Product: SYK
7. 4. MAP kinase output
8. ERK1/2 recruitment and c-FOS activationRegulatory Stepscimp_erk_output
  
  Annotons
  - ERK2 (MAPK1) Gene Product: MAPK1
  - ERK1 (MAPK3) Gene Product: MAPK3
9. 5. negative feedback optional
10. CSK negative feedbackRegulatory Stepscimp_csk_feedback
  
  Annotons
  - CSK inhibitory kinase Gene Product: CSK

Details

Context

mammalsNCBITaxon:40674

macrophageCL:0000235

SCIMP TLR tyrosine-kinase scaffoldSignaling Pathwayscimp_tlr_tyrosine_kinase_scaffold

toll-like receptor 4 signaling pathwayGO:0034142

Context

mammalsNCBITaxon:40674

macrophageCL:0000235

Connections

scimp_tlr4_receptor -> scimp_scaffold Causes

LPS-activated TLR4 binds SCIMP through its TIR domain.

scimp_scaffold -> scimp_tyrosine_kinase_relay Positively Regulates

SCIMP holds LYN and recruits SYK, bringing both to TLR4.

scimp_tyrosine_kinase_relay -> scimp_erk_output Positively Regulates

TLR4 Y672 phosphorylation starts ERK1/2 and c-FOS phosphorylation.

scimp_scaffold -> scimp_erk_output Positively Regulates

SCIMP directly scaffolds ERK1/2 at the receptor.

scimp_scaffold -> scimp_csk_feedback Positively Regulates

Phosphorylated SCIMP (pY96) recruits CSK to the membrane.

scimp_csk_feedback -> scimp_tyrosine_kinase_relay Negatively Regulates

CSK limits Src-family kinase activity at SCIMP.

Part 1: activated receptor

LPS-activated TLR4Regulatory Stepscimp_tlr4_receptor

TLR4 activated by LPS through MD-2 (modelled in tlr4_md2_lps_signaling). Here it is both the entry point and the substrate of the SCIMP-scaffolded kinases.

Annotons

TLR4 signaling receptor

scimp_branch_tlr4

Participant: Gene Product: TLR4

Gene Product:

TLR4UniProtKB:O00206

Function

signaling receptor activityGO:0038023

Processes

toll-like receptor 4 signaling pathwayGO:0034142

Locations

plasma membraneGO:0005886

Activated receptor whose TIR domain is bound by SCIMP and then tyrosine phosphorylated.

PMID:28098138

TLR4 associates with SCIMP only after LPS stimulation.

In addition, TLR4 co-immunoprecipitated with SCIMP, and in this case, the interaction was strictly LPS-induced

Part 2: transmembrane scaffold

SCIMP transmembrane scaffoldRegulatory Stepscimp_scaffold

SCIMP sits in lipid-raft and tetraspanin-rich membrane domains, concentrated in dorsal ruffles where TLR4 signals. It holds LYN constitutively and, once phosphorylated, docks SYK (pY96, pY120), GRB2 (pY58), CSK (pY96) and SLP65 (pY120).

Annotons

SCIMP signaling adaptor

scimp_adaptor

Participant: Gene Product: SCIMP

Gene Product:

SCIMPUniProtKB:Q6UWF3

Function

signaling adaptor activityGO:0035591

Processes

toll-like receptor 4 signaling pathwayGO:0034142

Locations

plasma membraneGO:0005886

Bridges TLR4 to LYN, SYK and ERK1/2; required for TLR4 tyrosine phosphorylation. Matches the SCIMP gene review core function.

PMID:28098138

SCIMP carries LYN and is required for TLR4 tyrosine phosphorylation.

In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40.

PMID:35337798

SCIMP recruits SYK after LPS activation of TLR4.

Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation.

Part 3: receptor tyrosine phosphorylation

LYN and SYK tyrosine kinasesRegulatory Stepscimp_tyrosine_kinase_relay

LYN, bound to SCIMP before stimulation, phosphorylates SCIMP; phospho-SCIMP then recruits SYK. Both kinases contribute to TLR4 TIR-domain phosphorylation, which strengthens the SCIMP-TLR4 interaction and initiates downstream signalling.

Annotons

LYN tyrosine kinase

scimp_branch_lyn

Participant: Gene Product: LYN

Gene Product:

LYNUniProtKB:P07948

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

Targets: SCIMPUniProtKB:Q6UWF3 TLR4UniProtKB:O00206

Processes

toll-like receptor 4 signaling pathwayGO:0034142

Locations

plasma membraneGO:0005886

SCIMP-bound Src-family kinase; phosphorylates SCIMP and TLR4.

PMID:21930792

SCIMP is constitutively associated with Lyn and becomes tyrosine phosphorylated on receptor stimulation.

In B cells, it is constitutively associated with Lyn kinase and becomes tyrosine phosphorylated after major histocompatibility complex type II (MHC-II) stimulation.

PMID:28098138

SCIMP-associated Lyn is needed for TLR4 tyrosine phosphorylation.

In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4

SYK tyrosine kinase

scimp_branch_syk

Participant: Gene Product: SYK

Gene Product:

SYKUniProtKB:P43405

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

Targets: TLR4UniProtKB:O00206 SCIMPUniProtKB:Q6UWF3

Processes

toll-like receptor 4 signaling pathwayGO:0034142

Locations

plasma membraneGO:0005886

Recruited by its tandem SH2 domains to SCIMP pY96 and pY120 in place of an ITAM; phosphorylates TLR4 and SCIMP.

PMID:35337798

SYK docks on two SCIMP phosphotyrosines and drives TLR phosphorylation.

Binding of the dual SH2 domains of Syk to the phosphorylated tyrosine sites of SCIMP at Y96 and Y120 promoted Syk activation, TLR phosphorylation, and signal amplification for inflammatory cytokine production.

PMID:37058370

SCIMP and SYK mediate TLR4 Y672 phosphorylation.

Our data also support a role for the TLR4-interacting membrane proteins SCIMP and the SYK kinase axis in mediating TLR4 Y672 phosphorylation to permit downstream inflammatory responses in murine macrophages.

Part 4: MAP kinase output

ERK1/2 recruitment and c-FOS activationRegulatory Stepscimp_erk_output

SCIMP recruits ERK1/2 to TLR4 in ruffles and macropinosomes. Phosphorylated TLR4 Y672 is needed for ERK1/2 and c-FOS phosphorylation, which drives the selective IL-6 and IL-12p40 output.

Annotons

ERK2 (MAPK1)

scimp_branch_mapk1

Participant: Gene Product: MAPK1

Gene Product:

MAPK1UniProtKB:P28482

Function

MAP kinase activityGO:0004707

Targets: FOSUniProtKB:P01100

Processes

ERK1 and ERK2 cascadeGO:0070371

Recruited to membrane TLR4 by SCIMP; phosphorylates c-FOS.

PMID:34496234

SCIMP directly scaffolds ERK1/2 in TLR pathways.

SCIMP is a direct scaffold for Erk1/2 in TLR pathways

PMID:34496234

Without SCIMP, ERK1/2 are not recruited to TLR4 and c-Fos is not activated.

SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production

PMID:37058370

TLR4 Y672 phosphorylation initiates ERK1/2 and c-FOS phosphorylation.

Y672 phosphorylation exerting its pro-inflammatory effects more selectively by initiating ERK1/2 and c-FOS phosphorylation

ERK1 (MAPK3)

scimp_branch_mapk3

Participant: Gene Product: MAPK3

Gene Product:

MAPK3UniProtKB:P27361

Function

MAP kinase activityGO:0004707

Targets: FOSUniProtKB:P01100

Processes

ERK1 and ERK2 cascadeGO:0070371

Paralog of ERK2 with the same role here; the studies do not separate the two.

PMID:34496234

SCIMP directly scaffolds ERK1/2 in TLR pathways.

SCIMP is a direct scaffold for Erk1/2 in TLR pathways

PMID:34496234

Without SCIMP, ERK1/2 are not recruited to TLR4 and c-Fos is not activated.

SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production

PMID:37058370

TLR4 Y672 phosphorylation initiates ERK1/2 and c-FOS phosphorylation.

Y672 phosphorylation exerting its pro-inflammatory effects more selectively by initiating ERK1/2 and c-FOS phosphorylation

Part 5: negative feedback (optional)

CSK negative feedbackRegulatory Stepscimp_csk_feedback

CSK docks on SCIMP pY96 and limits Src-family kinase activity. Shown for MHC-II signalling in B cells; CSK is also recruited to SCIMP after LPS in macrophages, but its effect on TLR4 output has not been measured, so the step is optional.

Annotons

CSK inhibitory kinase

scimp_branch_csk

Participant: Gene Product: CSK

Gene Product:

CSKUniProtKB:P41240

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

Locations

plasma membraneGO:0005886

Brought to the membrane by phospho-SCIMP, where it can inhibit SCIMP-bound LYN.

PMID:21930792

CSK binding to SCIMP is a negative regulatory loop.

While the association with SLP65 initiates the downstream signaling cascades, Csk binding functions as a negative regulatory loop.

PMID:28290451

LPS-induced SCIMP phosphorylation recruits GRB2, CSK and SLP65 in macrophages.

used to demonstrate the specificity of LPS/TLR4-induced, site-specific phosphorylation of SCIMP for the temporal recruitment of the effectors Grb2, Csk and SLP65.