Canonical Notch signaling pathway module

A cross-species decomposition of canonical (CSL-dependent) Notch signaling, a contact-dependent juxtacrine pathway present across eumetazoans. A membrane-bound DSL-type ligand on a signal-sending cell is ubiquitylated by a Mind bomb or Neuralized E3 ligase and endocytosed; the resulting pulling force on the bound Notch receptor of the neighboring cell unfolds its negative regulatory region, exposing the S2 site to an ADAM10-family metalloprotease. The membrane-tethered remnant is then cut within its transmembrane segment by gamma-secretase, releasing the Notch intracellular domain (NICD). NICD enters the nucleus, binds the DNA-bound CSL transcription factor (RBPJ, Su(H), LAG-1), and together with a Mastermind-family coactivator converts CSL from a corepressor-bound repressor into an activator of target genes, prominently the HES/E(spl) and HEY bHLH repressors. Receptor competence is set beforehand in the ER and Golgi by POFUT1-type O-fucosylation and, in arthropods and vertebrates, by Fringe elongation of those O-fucose glycans, which tunes receptor responsiveness to Delta- versus Serrate/Jagged-type ligands. The module is written so that each role is a union over the lineage-specific implementations found in vertebrates, insects, nematodes, and cnidarians.

MODULE:notch_signalingDRAFTSignaling Pathwaymodules/notch_signaling.yaml

Notch signaling pathwayGO:0007219

GO:0007219

Notch signaling pathway

The module is grounded in the GO biological process term for Notch signaling.

file:modules/notch_signaling-deep-research-falcon.md

Falcon module deep research on canonical Notch signaling

Provider deep research used for boundary setting: the obligatory trunk is trans DSL-Notch binding, force-dependent S2 exposure, ADAM S2 cleavage, gamma-secretase S3 cleavage, NICD-CSL-Mastermind assembly and target transcription; S1 furin processing, glycosylation, ligand E3 ligases and cis-inhibition are treated as maturation or regulatory context.

gomodel:60ad85f700000309

Notch signaling pathway via N-Dl (D.mel)

FlyBase production GO-CAM covering Delta ligand, Notch receptor, Kuzbanian S2 cleavage, Presenilin S3 cleavage and the NICD coactivator activity; the module trunk matches its causal order.

Reactome:R-HSA-212356

Formation of CSL-NICD coactivator complex

Reactome models the nuclear step as NICD binding RBPJ (CSL) and recruiting MAML.

Reactome:R-HSA-1912372

Fringe-modified Pre-NOTCH is cleaved by FURIN

Reactome places Fringe modification and furin S1 processing upstream of surface delivery of the mature receptor, i.e. in receptor maturation rather than in ligand-triggered activation.

Union modeling. Each role that is filled by different, often non-homologous, proteins in different lineages is a variant_set. selection ONE_OR_MORE is used where a single organism can deploy several implementations at once (Delta- and Serrate/Jagged-type ligands in flies and vertebrates; Mind bomb and Neuralized ligand E3s; HES/E(spl) and HEY target families), so a concrete realization is the union of the variants present. selection EXACTLY_ONE is used only for the Mastermind coactivator lineage, where each organism uses one of three sequence-unrelated or PANTHER-disjoint solutions. Optional parts (Fringe, CSL default repression, cis-inhibition) are absent from at least one well-studied lineage (C. elegans has no Fringe and no Hairless ortholog). PANTHER grounding. Concrete members were checked against the family reviews in interpro/panther/<PTHR>/<PTHR>-review.yaml written for this module. PANTHER classifies Notch receptors inconsistently: vertebrate NOTCH1-3, zebrafish notch1a and Nematostella Notch are in PTHR45836 (Notch clade node PTN001933897), but Drosophila N is in PTHR22804:SF57, C. elegans LIN-12 in PTHR24044:SF505 and GLP-1 in PTHR24033:SF232 (PANTHER 19 tree; InterPro/UniProt HMM scoring gives yet other families). The receptor descriptor therefore follows PTHR45836 and lists the out-of-family receptors as representative members deliberately. PAINT node PTN002371879 (Notch binding) belongs to the PTHR24044 tree, not PTHR45836, and is inherited by non-ligands (NEEDS_PRUNING in the PTHR24044 review), so it is not used as a ligand ancestry anchor. Presenilin's GO:0007219 node PTN000024430 is TOO_DEEP (Dictyostelium inherits it), so presenilin is anchored on its catalytic node only. Drosophila Mastermind is misclassified by PANTHER into the Mis18 family PTHR16431 and C. elegans SEL-8/LAG-3 has no PANTHER family, so those coactivators are grounded as concrete gene products.

28Nodes

14Parts

5Variant Sets

13Variants

22Annotons

11Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

notch_signaling-deep-research-falcon.md (falcon)

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

notch_s2_cleavage → notch_s3_cleavage [NOT_CHECKED]
The S2 product NEXT is the gamma-secretase substrate (protein intermediate, not a CoA carrier).

Function consistency and core coverage

47 gene-function check(s) reflected in core functions · 0 conflict(s) · 15 evidence or coverage gap(s) (67 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
pofut1_fucosyltransferase	POFUT1 (human) UniProtKB:Q9H488 Family Representative	peptide-O-fucosyltransferase activity GO:0046922	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pofut1_fucosyltransferase	O-fut1 (fly) UniProtKB:Q9V6X7 Family Representative	peptide-O-fucosyltransferase activity GO:0046922	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fringe_glcnac_transferase	LFNG (human) UniProtKB:Q8NES3 Family Representative	O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity GO:0033829	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fringe_glcnac_transferase	fng (fly) UniProtKB:Q24342 Family Representative	O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity GO:0033829	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
delta_ligand	DLL1 (human) UniProtKB:O00548 Family Representative	receptor ligand activity (Notch activation) GO:0048018	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
delta_ligand	Dll1 (mouse) UniProtKB:Q61483 Family Representative	receptor ligand activity (Notch activation) GO:0048018	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
delta_ligand	dla (zebrafish) UniProtKB:Q6DI48 Family Representative	receptor ligand activity (Notch activation) GO:0048018	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
delta_ligand	Dl (fly) UniProtKB:P10041 Family Representative	receptor ligand activity (Notch activation) GO:0048018	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
delta_ligand	Delta-like (Nematostella) UniProtKB:G9JWI6 Family Representative	receptor ligand activity (Notch activation) GO:0048018	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
jagged_ligand	JAG1 (human) UniProtKB:P78504 Family Representative	receptor ligand activity (Notch activation) GO:0048018	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
jagged_ligand	Ser (fly) UniProtKB:P18168 Family Representative	receptor ligand activity (Notch activation) GO:0048018	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nematode_dsl_ligand	lag-2 (worm) UniProtKB:P45442 Family Representative	receptor ligand activity (Notch activation) GO:0048018	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nematode_dsl_ligand	apx-1 (worm; PANTHER PTHR24044:SF502) UniProtKB:P41990 Family Representative	receptor ligand activity (Notch activation) GO:0048018	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dos_coligand	osm-11 (worm) UniProtKB:O45346 Family Representative	Notch binding GO:0005112	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mib1_ligase	MIB1 (human) UniProtKB:Q86YT6 Family Representative	ubiquitin protein ligase activity GO:0061630	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mib1_ligase	mib1 (zebrafish) UniProtKB:Q804S5 Family Representative	ubiquitin protein ligase activity GO:0061630	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mib1_ligase	mib1 (fly) UniProtKB:Q9VUX2 Family Representative	ubiquitin protein ligase activity GO:0061630	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
neur_ligase	neur (fly) UniProtKB:P29503 Family Representative	ubiquitin protein ligase activity GO:0061630	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
neur_ligase	NEURL1 (human) UniProtKB:O76050 Family Representative	ubiquitin protein ligase activity GO:0061630	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dll3_cis_inhibitor	Dll3 (mouse) UniProtKB:O88516 Gene	Notch binding GO:0005112	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
notch_receptor	NOTCH1 (human) UniProtKB:P46531 Family Representative	transmembrane signaling receptor activity GO:0004888	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
notch_receptor	Notch1 (mouse) UniProtKB:Q01705 Family Representative	transmembrane signaling receptor activity GO:0004888	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
notch_receptor	notch1a (zebrafish) UniProtKB:P46530 Family Representative	transmembrane signaling receptor activity GO:0004888	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
notch_receptor	Notch (Nematostella) UniProtKB:G9JWI5 Family Representative	transmembrane signaling receptor activity GO:0004888	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
notch_receptor	N (fly) UniProtKB:P07207 Family Representative	transmembrane signaling receptor activity GO:0004888	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
notch_receptor	lin-12 (worm) UniProtKB:P14585 Family Representative	transmembrane signaling receptor activity GO:0004888	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
notch_receptor	glp-1 (worm) UniProtKB:P13508 Family Representative	transmembrane signaling receptor activity GO:0004888	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
adam10_s2_protease	ADAM10 (human) UniProtKB:O14672 Family Representative	metalloendopeptidase activity GO:0004222	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
adam10_s2_protease	kuz (fly) UniProtKB:Q9VJW9 Family Representative	metalloendopeptidase activity GO:0004222	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
adam10_s2_protease	sup-17 (worm) UniProtKB:G5EFD9 Family Representative	metalloendopeptidase activity GO:0004222	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gamma_secretase_s3	PROTEIN_COMPLEX Gene	aspartic endopeptidase activity, intramembrane cleaving GO:0042500	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
gamma_secretase_s3/presenilin_unit	PSEN1 (human) UniProtKB:P49768 Family Representative	aspartic endopeptidase activity, intramembrane cleaving GO:0042500	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gamma_secretase_s3/presenilin_unit	Psn (fly) UniProtKB:O02194 Family Representative	aspartic endopeptidase activity, intramembrane cleaving GO:0042500	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gamma_secretase_s3/presenilin_unit	sel-12 (worm) UniProtKB:P52166 Family Representative	aspartic endopeptidase activity, intramembrane cleaving GO:0042500	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
csl_factor	RBPJ (human) UniProtKB:Q06330 Family Representative	DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
csl_factor	Rbpj (mouse) UniProtKB:P31266 Family Representative	DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
csl_factor	rbpjb (zebrafish) UniProtKB:A4FTT4 Family Representative	DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
csl_factor	Su(H) (fly) UniProtKB:P28159 Family Representative	DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
csl_factor	lag-1 (worm) UniProtKB:V6CLJ5 Family Representative	DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
csl_factor	CSL (Nematostella) UniProtKB:A7S478 Family Representative	DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
nicd_coactivator	Notch intracellular domain (NICD) of N (fly) UniProtKB:P07207 Gene	transcription coactivator activity GO:0003713	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
maml_coactivator	MAML1 (human) UniProtKB:Q92585 Family Representative	transcription coactivator activity GO:0003713	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
maml_coactivator	Mastermind-like (Nematostella) UniProtKB:A7SLJ1 Family Representative	transcription coactivator activity GO:0003713	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
fly_mam_coactivator	mam (fly) UniProtKB:P21519 Gene	transcription coactivator activity GO:0003713	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
lag3_coactivator	sel-8/lag-3 (worm) UniProtKB:Q09260 Gene	transcription coactivator activity GO:0003713	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hairless_adaptor	H (fly) UniProtKB:Q02308 Gene	transcription corepressor activity GO:0003714	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
spen_adaptor	SPEN (human) UniProtKB:Q96T58 Gene	transcription corepressor activity GO:0003714	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
hes_repressor	HES1 (human) UniProtKB:Q14469 Family Representative	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hes_repressor	Hes7 (mouse) UniProtKB:Q8BKT2 Family Representative	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hes_repressor	her1 (zebrafish) UniProtKB:Q90463 Family Representative	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hes_repressor	E(spl)m8-HLH (fly) UniProtKB:P13098 Family Representative	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hey_repressor	HEY1 (human) UniProtKB:Q9Y5J3 Family Representative	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
pofut1_fucosyltransferase	POFUT1/O-fut1 protein O-fucosyltransferases PANTHER:PTHR21420 Family	peptide-O-fucosyltransferase activity GO:0046922	Family Supported Family review supports GO:0046922 FAMILY_WIDE. Single-copy orthologs with conserved activity; the ecdysozoan members (SF10) should receive it too, which requires moving the IBD node up one level.
fringe_glcnac_transferase	Fringe glycosyltransferases PANTHER:PTHR10811 Family	O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity GO:0033829	Family Scope Restricted GO:0033829 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. Fringe subfamilies only. SF5 is listed because it contains Drosophila Fringe; its plant and protist members lie outside the Fringe clade and should not receive the term. The node-level grant at PTN000087518 already achieves the correct scope.
delta_ligand	Delta/DLL ligands (PANTHER Notch ligand family, Delta clade) PANTHER:PTHR24044 Family	receptor ligand activity (Notch activation) GO:0048018	Family Function Unreviewed The family review has no applicable adjudication supporting or excluding GO:0048018.
jagged_ligand	Serrate/Jagged ligands (PANTHER Notch ligand family, Jagged clade) PANTHER:PTHR24044 Family	receptor ligand activity (Notch activation) GO:0048018	Family Function Unreviewed The family review has no applicable adjudication supporting or excluding GO:0048018.
nematode_dsl_ligand	Nematode DSL ligands PANTHER:PTHR22669 Family	receptor ligand activity (Notch activation) GO:0048018	Family Function Unreviewed The family review has no applicable adjudication supporting or excluding GO:0048018.
dos_coligand	OSM-11-type DOS co-ligands PANTHER:PTHR35015 Family	Notch binding GO:0005112	Family Review Missing No supported structured family review is available for PANTHER:PTHR35015.
mib1_ligase	Mind bomb MIB1 clade PANTHER:PTHR24202:SF53 Family	ubiquitin protein ligase activity GO:0061630	Family Supported Family review supports GO:0061630 FAMILY_WIDE. Every full-length member has C-terminal RING fingers. The RING-less HERC2P3 fragment is a known exception and should not be taken to mean the family lacks the activity.
neur_ligase	Neuralized (NEUR/NEURL1/NEURL1B) PANTHER:PTHR12429 Family	ubiquitin protein ligase activity GO:0061630	Family Scope Restricted GO:0061630 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. Restricted to NHR-RING subfamilies (verified RING PF13920 in neur, NEURL1, NEURL1B, NEURL3). NEURL2 (NHR + SOCS box) and NEURL4 (NHR only) lack the RING. SF36/SF37 (both officially "E3 UBIQUITIN-PROTEIN LIGASE NEURL3") were not checked and are not listed.
notch_receptor	Notch receptors PANTHER:PTHR45836 Family	transmembrane signaling receptor activity GO:0004888	Family Function Unreviewed The family review has no applicable adjudication supporting or excluding GO:0004888.
adam10_s2_protease	ADAM10/ADAM17 metalloproteases PANTHER:PTHR45702 Family	metalloendopeptidase activity GO:0004222	Family Supported Family review supports GO:0004222 FAMILY_WIDE. The zinc catalytic motif is intact in every model-organism member examined, and both paralog groups have direct protease activity.
presenilin_unit	Presenilins PANTHER:PTHR10202 Family	aspartic endopeptidase activity, intramembrane cleaving GO:0042500	Family Function Unreviewed The family review has no applicable adjudication supporting or excluding GO:0042500.
csl_factor	CSL transcription factors PANTHER:PTHR10665 Family	DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981	Family Supported Family review supports GO:0000981 FAMILY_WIDE. Fungal and metazoan CSL proteins, including Notch-independent RBPJL, are sequence-specific DNA-binding transcription factors.
maml_coactivator	Mastermind-like proteins PANTHER:PTHR15692 Family	transcription coactivator activity GO:0003713	Family Function Unreviewed The family review has no applicable adjudication supporting or excluding GO:0003713.
hes_repressor	HES/E(spl) bHLH-Orange repressors PANTHER:PTHR10985 Family	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Family Function Unreviewed Family review leaves GO:0000981 UNRESOLVED. Zebrafish Hes6 contributes to a DNA-binding repressor with Her7. This does not imply autonomous Hes6 homodimer binding, and the evidence does not grant identical activity to all HES/HEY products or all possible dimer combinations.
hey_repressor	HEY bHLH-Orange repressors PANTHER:PTHR10985:SF78 Family	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Family Function Unreviewed Family review leaves GO:0000981 UNRESOLVED. Zebrafish Hes6 contributes to a DNA-binding repressor with Her7. This does not imply autonomous Hes6 homodimer binding, and the evidence does not grant identical activity to all HES/HEY products or all possible dimer combinations.

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.

notch_cis_inhibition ⊣ notch_receptor_engagement [input]
notch_cis_inhibition is a negative regulator with no upstream edge (not described as feedback)
csl_default_repression ⊣ csl_dna_binding [input]
csl_default_repression is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (49/54 grounded genes reviewed)

43 complete review(s) · 45 with deep research · 5 missing review · 4 reviewed but lacking deep research

Gene	Review	Complete	Deep research
CSL (Nematostella) A7S478	✗	—	—
Mastermind-like (Nematostella) A7SLJ1	✗	—	—
ADAM10 O14672	✓	✓	✗
APH1A Q96BI3	✓	✓	✓
apx-1 P41990	✓	26/28	✓
delta G9JWI6	✓	✓	✓
Dl P10041	✓	✓	✓
dla Q6DI48	✓	✓	✓
DLL1 O00548	✓	✓	✓
Dll1 Q61483	✓	✓	✓
Dll3 O88516	✓	✓	✓
E(spl)m8-HLH P13098	✓	✓	✓
fng Q24342	✓	✓	✓
glp-1 P13508	✓	✓	✓
H Q02308	✓	✓	✓
her1 Q90463	✓	✓	✓
HES1 Q14469	✓	113/126	✓
Hes7 Q8BKT2	✓	✓	✓
JAG1 P78504	✓	✓	✓
kuz Q9VJW9	✓	✓	✓
lag-1 V6CLJ5	✓	✓	✓
lag-2 P45442	✓	✓	✓
LFNG Q8NES3	✓	✓	✓
lin-12 P14585	✓	✓	✓
mam P21519	✓	✓	✓
MAML1 Q92585	✓	✓	✓
mib1 Q804S5	✓	✓	✓
MIB1 Q86YT6	✓	✓	✓
mib1 Q9VUX2	✓	✓	✓
N P07207	✓	✓	✓
NCSTN Q92542	✓	✓	✗
neur P29503	✓	✓	✓
NEURL1 O76050	✓	✓	✓
notch G9JWI5	✓	✓	✓
NOTCH1 P46531	✓	377/378	✓
Notch1 Q01705	✓	450/453	✓
notch1a P46530	✓	✓	✓
Ofut1 Q9V6X7	✓	✓	✓
osm-11 O45346	✓	✓	✓
lst-1 (worm) P91820	✗	—	—
POFUT1 Q9H488	✓	✓	✓
PSEN1 P49768	✓	181/197	✗
PSENEN Q9NZ42	✓	✓	✗
Psn O02194	✓	✓	✓
SPEN (human) Q96T58	✗	—	—
HEY1 (human) Q9Y5J3	✗	—	—
Rbpj P31266	✓	✓	✓
RBPJ Q06330	✓	✓	✓
rbpjb A4FTT4	✓	✓	✓
sel-12 P52166	✓	28/29	✓
sel-8 Q09260	✓	✓	✓
Ser P18168	✓	✓	✓
Su(H) P28159	✓	✓	✓
sup-17 G5EFD9	✓	✓	✓

Tree

Canonical Notch signaling pathwaySignaling Pathwaynotch_signaling

Parts
1. 1. receptor maturation (signal-receiving cell, secretory pathway)
2. Notch receptor O-glycan maturationBiological Processnotch_receptor_maturation
  
  Parts
  1. 1. EGF-repeat O-fucosylation
  2. POFUT1-mediated O-fucosylation of Notch EGF repeatsReactionnotch_o_fucosylation
    
    Annotons
    
    Protein O-fucosyltransferase 1 Family: POFUT1/O-fut1 protein O-fucosyltransferases
  3. 2. Fringe elongation of O-fucose (arthropods and vertebrates) optional
  4. Fringe GlcNAc elongation of Notch O-fucoseReactionnotch_fringe_elongation
    
    Annotons
    
    Fringe O-fucosylpeptide GlcNAc-transferase Family: Fringe glycosyltransferases
3. 1. ligand presentation and activation (signal-sending cell)
4. DSL ligand presentation and E3-dependent activationBiological Processnotch_ligand_presentation
  
  Variants
  1. Activating ligand class by ligand structural class / lineage (One Or More)
    
    Delta-type ligandMolecular Functiondelta_type_ligand
    
    Annotons
    
    Delta/Delta-like activating ligand Family: Delta/DLL ligands (PANTHER Notch ligand family, Delta clade)
    
    Serrate/Jagged-type ligandMolecular Functionserrate_jagged_type_ligand
    
    Annotons
    
    Serrate/Jagged activating ligand Family: Serrate/Jagged ligands (PANTHER Notch ligand family, Jagged clade)
    
    Nematode DSL ligand plus secreted DOS co-ligandMolecular Functionnematode_bipartite_ligand
    
    Annotons
    
    Nematode DSL transmembrane ligand Family: Nematode DSL ligands
    
    Secreted DOS-motif co-ligand Family: OSM-11-type DOS co-ligands
  2. Ligand-activating E3 ubiquitin ligase by E3 ligase family (structurally unrelated) (One Or More)
    
    Mind bomb (MIB1-type) E3Molecular Functionmind_bomb_e3
    
    Annotons
    
    Mind bomb ligand E3 ligase Family: Mind bomb MIB1 clade
    
    Neuralized E3Molecular Functionneuralized_e3
    
    Annotons
    
    Neuralized ligand E3 ligase Family: Neuralized (NEUR/NEURL1/NEURL1B)
5. 1. ligand cis-inhibition (same-cell) optional
6. Cis-inhibition of Notch by ligands in the receiving cellRegulatory Stepnotch_cis_inhibition
  
  Annotons
  - DLL3 cis-inhibitory ligand Gene Product: Dll3 (mouse)
7. 2. receptor engagement (signal-receiving cell)
8. Notch receptor binds ligand in transRegulatory Stepnotch_receptor_engagement
  
  Annotons
  - Notch receptor Family: Notch receptors
9. 3. S2 ectodomain cleavage
10. ADAM10-family S2 cleavage of NotchReactionnotch_s2_cleavage
  
  Annotons
  - ADAM10/Kuzbanian S2 protease Family: ADAM10/ADAM17 metalloproteases
11. 4. S3 intramembrane cleavage and NICD release
12. Gamma-secretase S3 cleavage releasing NICDReactionnotch_s3_cleavage
  
  Annotons
  - Gamma-secretase complex Protein Complex: gamma-secretase complex
13. 5. CSL transcriptional switch (nucleus)
14. NICD-CSL-Mastermind transcriptional activationRegulatory Stepnotch_csl_switch
  
  Parts
  1. 1. CSL DNA-binding platform
  2. CSL DNA-binding transcription factorMolecular Functioncsl_dna_binding
    
    Annotons
    
    CSL (RBPJ/Su(H)/LAG-1) Family: CSL transcription factors
  3. 2. NICD coactivation
  4. NICD as CSL-bound coactivatorMolecular Functionnicd_coactivation
    
    Annotons
    
    Notch intracellular domain Gene Product: Notch intracellular domain (NICD) of N (fly)
  5. 3. Mastermind-family coactivator
  6. Mastermind-family coactivator recruitmentMolecular Functionmastermind_coactivation
    
    Variants
    
    Mastermind coactivator lineage by taxon / sequence lineage (Exactly One)
    
    MAML-family coactivatorMolecular Functionmaml_family_coactivator
    
    Annotons
    
    Mastermind-like coactivator Family: Mastermind-like proteins
    
    Dipteran MastermindMolecular Functiondipteran_mastermind_coactivator
    
    Annotons
    
    Drosophila Mastermind Gene Product: mam (fly)
    
    Nematode LAG-3/SEL-8Molecular Functionnematode_lag3_coactivator
    
    Annotons
    
    LAG-3/SEL-8 Gene Product: sel-8/lag-3 (worm)
  7. default CSL repression (ligand-off state) optional
  8. Corepressor-bound CSL in the absence of NICDRegulatory Stepcsl_default_repression
    
    Variants
    
    CSL corepressor adaptor by taxon / corepressor family (One Or More)
    
    Insect HairlessMolecular Functionhairless_corepressor
    
    Annotons
    
    Hairless Gene Product: H (fly)
    
    Vertebrate SPEN/SHARPMolecular Functionspen_corepressor
    
    Annotons
    
    SPEN/SHARP Gene Product: SPEN (human)
15. 6. primary transcriptional output
16. Notch target gene outputRegulatory Stepnotch_target_output
  
  Variants
  1. Direct target class by target family / lineage (One Or More)
    
    HES/E(spl) bHLH repressorsMolecular Functionhes_espl_output
    
    Annotons
    
    HES/E(spl) repressor Family: HES/E(spl) bHLH-Orange repressors
    
    HEY bHLH repressorsMolecular Functionhey_output
    
    Annotons
    
    HEY repressor Family: HEY bHLH-Orange repressors
    
    Nematode germline stem-cell targetsModulenematode_germline_output
    
    Annotons
    
    LST-1 Gene Product: lst-1 (worm)

Details

Context

EumetazoaNCBITaxon:6072

plasma membraneGO:0005886 nucleusGO:0005634

Canonical Notch signaling pathwaySignaling Pathwaynotch_signaling

Notch signaling pathwayGO:0007219

Context

EumetazoaNCBITaxon:6072

plasma membraneGO:0005886 nucleusGO:0005634

Connections

notch_receptor_maturation -> notch_receptor_engagement Provides Input For

Glycosylated, folded receptor is delivered to the surface; Fringe status sets ligand preference.

notch_ligand_presentation -> notch_receptor_engagement Causes

Activated ligand binds the receptor in trans and applies endocytic pulling force.

notch_cis_inhibition -> notch_receptor_engagement Negatively Regulates

Cis ligand-receptor interactions sequester the receptor from trans activation.

notch_receptor_engagement -> notch_s2_cleavage Causes

Unfolding of the negative regulatory region exposes the S2 site.

notch_s2_cleavage -> notch_s3_cleavage Precedes

NEXT is the obligate gamma-secretase substrate.

notch_s3_cleavage -> notch_csl_switch Causes

Released NICD enters the nucleus and binds CSL.

notch_csl_switch -> notch_target_output Causes

The NICD-CSL-Mastermind complex activates target gene transcription.

Part 1: receptor maturation (signal-receiving cell, secretory pathway)

Notch receptor O-glycan maturationBiological Processnotch_receptor_maturation

Before reaching the surface, Notch EGF repeats are O-fucosylated in the ER by POFUT1/O-fut1, which also acts as a Notch-selective folding chaperone. In arthropods and vertebrates, Fringe enzymes in the Golgi extend O-fucose with GlcNAc, raising responsiveness to Delta-type and lowering responsiveness to Serrate/Jagged-type ligands. Vertebrate receptors are also cleaved at S1 by furin; this constitutive step produces the heterodimer but does not activate signaling and is not modeled as a separate part.

Connections

notch_o_fucosylation -> notch_fringe_elongation Provides Input For

Fringe elongates only O-fucose already added by POFUT1/O-fut1.

Part 1: EGF-repeat O-fucosylation

POFUT1-mediated O-fucosylation of Notch EGF repeatsReactionnotch_o_fucosylation

Annotons

Protein O-fucosyltransferase 1

pofut1_fucosyltransferase

Participant: Family: POFUT1/O-fut1 protein O-fucosyltransferases

Family:

POFUT1/O-fut1 protein O-fucosyltransferasesPANTHER:PTHR21420

Representative Members: POFUT1 (human)UniProtKB:Q9H488 O-fut1 (fly)UniProtKB:Q9V6X7

Function

peptide-O-fucosyltransferase activityGO:0046922

Substrates: GDP-L-fucose Notch EGF repeat (C2-X4-5-S/T-C3 consensus)

Products: O-fucosylated Notch EGF repeat

Processes

protein O-linked glycosylation via fucoseGO:0036066

Locations

endoplasmic reticulumGO:0005783

Adds O-fucose to Notch EGF repeats; fly O-fut1 also acts as a catalysis-independent Notch folding chaperone.

file:genes/DROME/O-fut1/O-fut1-ai-review.yaml

Gene review: core functions peptide-O-fucosyltransferase activity and a catalysis-independent Notch chaperone activity.

Part 2: Fringe elongation of O-fucose (arthropods and vertebrates) (optional)

Fringe GlcNAc elongation of Notch O-fucoseReactionnotch_fringe_elongation

Fringe beta-1,3-N-acetylglucosaminyltransferases act in the Golgi on POFUT1-generated O-fucose. Absent from C. elegans.

Annotons

Fringe O-fucosylpeptide GlcNAc-transferase

fringe_glcnac_transferase

Participant: Family: Fringe glycosyltransferases

Family:

Fringe glycosyltransferasesPANTHER:PTHR10811

Representative Members: LFNG (human)UniProtKB:Q8NES3 fng (fly)UniProtKB:Q24342

Function

O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activityGO:0033829

Processes

regulation of Notch signaling pathwayGO:0008593

Locations

Golgi membraneGO:0000139

Ligand-selectivity modifier; potentiates Delta-type and attenuates Serrate/Jagged-type signaling.

Part 1: ligand presentation and activation (signal-sending cell)

DSL ligand presentation and E3-dependent activationBiological Processnotch_ligand_presentation

The sending cell presents a membrane-tethered DSL-type ligand. Ligand ubiquitylation by Mind bomb and/or Neuralized drives epsin/clathrin endocytosis, which supplies the pulling force required to activate the bound receptor; ligands lacking this activation behave as inhibitors.

Connections

ligand_activating_e3 -> dsl_ligand_class Positively Regulates

Ligand ubiquitylation and endocytosis license DSL ligands to activate Notch in trans.

Variant set: Activating ligand class by ligand structural class / lineage (One Or More)

Union: flies and vertebrates deploy both Delta- and Serrate/Jagged-type ligands; nematodes use DSL-only transmembrane ligands with a separate secreted DOS co-ligand. Cnidarians have Delta-like ligands.

Delta-type ligandMolecular Functiondelta_type_ligand

Annotons

Delta/Delta-like activating ligand

delta_ligand

Participant: Family: Delta/DLL ligands (PANTHER Notch ligand family, Delta clade)

Family:

Delta/DLL ligands (PANTHER Notch ligand family, Delta clade)PANTHER:PTHR24044 Nematostella Delta-like (G9JWI6) is classified by PANTHER in PTHR24049:SF30 and is included as the cnidarian representative of the Delta architecture (MNNL, DSL, EGF repeats, transmembrane segment).

Representative Members: DLL1 (human)UniProtKB:O00548 Dll1 (mouse)UniProtKB:Q61483 dla (zebrafish)UniProtKB:Q6DI48 Dl (fly)UniProtKB:P10041 Delta-like (Nematostella)UniProtKB:G9JWI6

Function

receptor ligand activity (Notch activation)GO:0048018

Targets: Notch receptor EGF repeats 11-12

Processes

Notch signaling pathwayGO:0007219

Locations

plasma membraneGO:0005886

Trans-activating ligand; carries DSL domain and (DLL1, Dl) a DOS motif in EGF repeats 1-2.

Serrate/Jagged-type ligandMolecular Functionserrate_jagged_type_ligand

Annotons

Serrate/Jagged activating ligand

jagged_ligand

Participant: Family: Serrate/Jagged ligands (PANTHER Notch ligand family, Jagged clade)

Family:

Serrate/Jagged ligands (PANTHER Notch ligand family, Jagged clade)PANTHER:PTHR24044 Jagged-type ligands carry an extra cysteine-rich region; their clade (PTN000621015) has no PAINT annotation, so no ancestral node is asserted.

Representative Members: JAG1 (human)UniProtKB:P78504 Ser (fly)UniProtKB:P18168

Function

receptor ligand activity (Notch activation)GO:0048018

Targets: Notch receptor (binding via the DSL/MNNL module, GO:0005112 Notch binding)

Processes

Notch signaling pathwayGO:0007219

Locations

plasma membraneGO:0005886

Trans-activating ligand whose signaling is attenuated by Fringe modification of the receptor.

Nematode DSL ligand plus secreted DOS co-ligandMolecular Functionnematode_bipartite_ligand

C. elegans DSL ligands lack the DOS motif; that function is supplied in trans by secreted DOS-motif proteins such as OSM-11, which lack a DSL domain. The worm DSL ligands are split between the Caenorhabditis-specific PTHR22669 and PTHR24044:SF502.

Annotons

Nematode DSL transmembrane ligand

nematode_dsl_ligand

Participant: Family: Nematode DSL ligands

Family:

Nematode DSL ligandsPANTHER:PTHR22669

Representative Members: lag-2 (worm)UniProtKB:P45442 apx-1 (worm; PANTHER PTHR24044:SF502)UniProtKB:P41990

Function

receptor ligand activity (Notch activation)GO:0048018

Targets: Notch receptor (binding via the DSL/MNNL module, GO:0005112 Notch binding)

Processes

Notch signaling pathwayGO:0007219

Locations

plasma membraneGO:0005886

DSL-only ligand (e.g. LAG-2 from the distal tip cell niche, APX-1 from P2 in the 4-cell embryo).

Secreted DOS-motif co-ligand

dos_coligand

Participant: Family: OSM-11-type DOS co-ligands

Family:

OSM-11-type DOS co-ligandsPANTHER:PTHR35015

Representative Members: osm-11 (worm)UniProtKB:O45346

Function

Notch bindingGO:0005112

Processes

positive regulation of Notch signaling pathwayGO:0045747

Locations

extracellular regionGO:0005576

Diffusible co-ligand supplying the DOS function in trans; mammalian DLK1 can substitute for it.

Variant set: Ligand-activating E3 ubiquitin ligase by E3 ligase family (structurally unrelated) (One Or More)

Union: Mind bomb and Neuralized are unrelated E3 families that can substitute for each other on DSL ligand tails. Flies use both (neur in SOP lineages, mib1 broadly; loss of both abolishes DSL signaling); in mice MIB1 alone is required. The C. elegans ligand E3 is unresolved (see knowledge_gaps).

Mind bomb (MIB1-type) E3Molecular Functionmind_bomb_e3

Annotons

Mind bomb ligand E3 ligase

mib1_ligase

Participant: Family: Mind bomb MIB1 clade

Family:

Mind bomb MIB1 cladePANTHER:PTHR24202:SF53

Representative Members: MIB1 (human)UniProtKB:Q86YT6 mib1 (zebrafish)UniProtKB:Q804S5 mib1 (fly)UniProtKB:Q9VUX2

Function

ubiquitin protein ligase activityGO:0061630

Substrates: DSL ligand intracellular domain lysines

Processes

Notch signaling pathwayGO:0007219 endocytosisGO:0006897

Locations

cytoplasmGO:0005737

Ubiquitylates ligand tails to trigger force-generating ligand endocytosis.

Neuralized E3Molecular Functionneuralized_e3

Annotons

Neuralized ligand E3 ligase

neur_ligase

Participant: Family: Neuralized (NEUR/NEURL1/NEURL1B)

Family:

Neuralized (NEUR/NEURL1/NEURL1B)PANTHER:PTHR12429

Representative Members: neur (fly)UniProtKB:P29503 NEURL1 (human)UniProtKB:O76050

Function

ubiquitin protein ligase activityGO:0061630

Processes

regulation of Notch signaling pathwayGO:0008593

Locations

plasma membraneGO:0005886

Dominant ligand E3 in Drosophila SOP lineages; minor or redundant with MIB1 in mammals.

Part 1: ligand cis-inhibition (same-cell) (optional)

Cis-inhibition of Notch by ligands in the receiving cellRegulatory Stepnotch_cis_inhibition

Ligand and receptor expressed in the same cell interact in cis and inhibit signaling. Activating ligands (DLL1, Dl, Ser) cis-inhibit as a side activity; mammalian DLL3 is a dedicated non-activating ligand that binds Notch in the Golgi and late endosomes and does not activate Notch in trans.

Annotons

DLL3 cis-inhibitory ligand

dll3_cis_inhibitor

Participant: Gene Product: Dll3 (mouse)

Gene Product:

Dll3 (mouse)UniProtKB:O88516

Function

Notch bindingGO:0005112

Processes

negative regulation of Notch signaling pathwayGO:0045746

Locations

Golgi apparatusGO:0005794

Vertebrate-specific divergent Delta (degenerate DSL domain, no intracellular lysines) acting only in cis.

file:genes/mouse/Dll3/Dll3-ai-review.yaml

Gene review core function Notch binding in cis, negative regulation of Notch signaling, Golgi/late endosome.

Part 2: receptor engagement (signal-receiving cell)

Notch receptor binds ligand in transRegulatory Stepnotch_receptor_engagement

A single-pass Notch receptor (EGF repeats, LNR-containing negative regulatory region, RAM, ankyrin repeats, PEST) on the receiving cell binds the sending cell's ligand; endocytic pulling unfolds the negative regulatory region and exposes the S2 site.

Annotons

Notch receptor

notch_receptor

Participant: Family: Notch receptors

Family:

Notch receptorsPANTHER:PTHR45836 PANTHER's Notch clade (PTN001933897) sits in PTHR45836 with Slit and other LRR proteins. PANTHER's sequence classification places Drosophila N in PTHR22804:SF57, C. elegans LIN-12 in PTHR24044:SF505, GLP-1 in PTHR24033:SF232 and zebrafish notch1a in PTHR12916:SF9 (InterPro HMM scoring puts notch1a in PTHR45836:SF23); these are listed deliberately as out-of-family representatives of a functional receptor grouping.

Representative Members: NOTCH1 (human)UniProtKB:P46531 Notch1 (mouse)UniProtKB:Q01705 notch1a (zebrafish)UniProtKB:P46530 Notch (Nematostella)UniProtKB:G9JWI5 N (fly)UniProtKB:P07207 lin-12 (worm)UniProtKB:P14585 glp-1 (worm)UniProtKB:P13508

Function

transmembrane signaling receptor activityGO:0004888

Processes

Notch signaling pathwayGO:0007219

Locations

plasma membraneGO:0005886

Receiver whose ligand-induced cleavage releases the nuclear effector; one receptor in flies, two partially redundant paralogs in C. elegans, four in mammals.

Part 3: S2 ectodomain cleavage

ADAM10-family S2 cleavage of NotchReactionnotch_s2_cleavage

The exposed juxtamembrane S2 site is cut by an ADAM10-family metalloprotease, shedding the ectodomain and leaving the membrane-tethered NEXT fragment. ADAM10/Kuzbanian/SUP-17 is the physiological ligand-dependent sheddase; ADAM17/Tace/ADM-4 contributes mainly in ligand-independent or redundant settings.

Notch receptor processingGO:0007220

Annotons

ADAM10/Kuzbanian S2 protease

adam10_s2_protease

Participant: Family: ADAM10/ADAM17 metalloproteases

Family:

ADAM10/ADAM17 metalloproteasesPANTHER:PTHR45702

Representative Members: ADAM10 (human)UniProtKB:O14672 kuz (fly)UniProtKB:Q9VJW9 sup-17 (worm)UniProtKB:G5EFD9

Function

metalloendopeptidase activityGO:0004222

Substrates: ligand-bound Notch receptor (S2 site)

Products: Notch extracellular truncation (NEXT)

Processes

Notch receptor processingGO:0007220 Notch signaling pathwayGO:0007219

Locations

plasma membraneGO:0005886

Cell-autonomous S2 sheddase acting in the Notch-receiving cell.

Part 4: S3 intramembrane cleavage and NICD release

Gamma-secretase S3 cleavage releasing NICDReactionnotch_s3_cleavage

Gamma-secretase cleaves NEXT within its transmembrane segment at S3, releasing the Notch intracellular domain (NICD), at the plasma membrane or after endocytosis.

Notch receptor processingGO:0007220

Annotons

Gamma-secretase complex

gamma_secretase_s3

Participant: Protein Complex: gamma-secretase complex

Protein Complex:

gamma-secretase complexGO:0070765

Active units:

Presenilin (catalytic)

Participant: Family: Presenilins

Family:

PresenilinsPANTHER:PTHR10202

Representative Members: PSEN1 (human)UniProtKB:P49768 Psn (fly)UniProtKB:O02194 sel-12 (worm)UniProtKB:P52166

Role: catalytic aspartyl protease subunit

Function:

aspartic endopeptidase activity, intramembrane cleavingGO:0042500

Nicastrin

Participant: Family: Nicastrin

Family:

NicastrinPANTHER:PTHR21092

Representative Members: NCSTN (human)UniProtKB:Q92542

Role: substrate-recruiting scaffold subunit

APH-1

Participant: Family: APH-1

Family:

APH-1PANTHER:PTHR12889

Representative Members: APH1A (human)UniProtKB:Q96BI3

Role: scaffold subunit

PEN-2

Participant: Family: PEN-2

Family:

PEN-2PANTHER:PTHR16318

Representative Members: PSENEN (human)UniProtKB:Q9NZ42

Role: presenilin-activating subunit

Function

aspartic endopeptidase activity, intramembrane cleavingGO:0042500

Substrates: Notch extracellular truncation (NEXT)

Products: Notch intracellular domain (NICD)

Processes

Notch receptor processingGO:0007220

Irreversible intramembrane cleavage converting the receptor into a nuclear effector.

Part 5: CSL transcriptional switch (nucleus)

NICD-CSL-Mastermind transcriptional activationRegulatory Stepnotch_csl_switch

NICD binds DNA-bound CSL through its RAM domain; a Mastermind-family coactivator then binds the composite NICD-ankyrin/CSL surface, and the ternary complex recruits p300/CBP and Mediator to activate targets.

CSL-Notch-Mastermind transcription factor complexGO:1990433

Connections

csl_default_repression -> csl_dna_binding Negatively Regulates

Corepressor adaptors hold CSL in the repressive state until NICD arrives.

nicd_coactivation -> mastermind_coactivation Precedes

NICD-CSL binding creates the composite surface that Mastermind recognizes.

Part 1: CSL DNA-binding platform

CSL DNA-binding transcription factorMolecular Functioncsl_dna_binding

Annotons

CSL (RBPJ/Su(H)/LAG-1)

csl_factor

Participant: Family: CSL transcription factors

Family:

CSL transcription factorsPANTHER:PTHR10665

Representative Members: RBPJ (human)UniProtKB:Q06330 Rbpj (mouse)UniProtKB:P31266 rbpjb (zebrafish)UniProtKB:A4FTT4 Su(H) (fly)UniProtKB:P28159 lag-1 (worm)UniProtKB:V6CLJ5 CSL (Nematostella)UniProtKB:A7S478

Function

DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981

Targets: CSL site (C/TGTGGGAA) in Notch-responsive enhancers

Processes

Notch signaling pathwayGO:0007219

Locations

nucleusGO:0005634

Sequence-specific platform that is a repressor without NICD and an activator with NICD and Mastermind. Vertebrate RBPJL is a Notch-independent PTF1 subunit and is not a member of this role.

Part 2: NICD coactivation

NICD as CSL-bound coactivatorMolecular Functionnicd_coactivation

Annotons

Notch intracellular domain

nicd_coactivator

Participant: Gene Product: Notch intracellular domain (NICD) of N (fly)

Gene Product:

Notch intracellular domain (NICD) of N (fly)UniProtKB:P07207 Processed intracellular fragment of any Notch receptor in the receptor-engagement part; fly N is used as the GO-CAM-grounded exemplar.

Function

transcription coactivator activityGO:0003713

Processes

positive regulation of transcription of Notch receptor targetGO:0007221

Locations

nucleusGO:0005634

RAM domain binds CSL; ankyrin repeats form the Mastermind docking surface.

Part 3: Mastermind-family coactivator

Mastermind-family coactivator recruitmentMolecular Functionmastermind_coactivation

Variant set: Mastermind coactivator lineage by taxon / sequence lineage (Exactly One)

Each organism uses one Mastermind solution: MAML-family proteins (vertebrates, cnidarians, most insects), the dipteran Mastermind (true homolog, but misclassified by PANTHER into the Mis18 family PTHR16431), or nematode LAG-3/SEL-8 (Pfam PF11498 Activator_LAG-3, no PANTHER family; homology to MAML unresolved).

MAML-family coactivatorMolecular Functionmaml_family_coactivator

Annotons

Mastermind-like coactivator

maml_coactivator

Participant: Family: Mastermind-like proteins

Family:

Mastermind-like proteinsPANTHER:PTHR15692

Representative Members: MAML1 (human)UniProtKB:Q92585 Mastermind-like (Nematostella)UniProtKB:A7SLJ1

Function

transcription coactivator activityGO:0003713

Locations

nucleusGO:0005634

Binds the NICD-CSL composite surface and recruits p300/CBP.

Dipteran MastermindMolecular Functiondipteran_mastermind_coactivator

Annotons

Drosophila Mastermind

fly_mam_coactivator

Participant: Gene Product: mam (fly)

Gene Product:

mam (fly)UniProtKB:P21519

Function

transcription coactivator activityGO:0003713

Locations

nucleusGO:0005634

MamL-1-domain coactivator; its PANTHER placement in PTHR16431 (Mis18) is a classification artefact, and the centromere IBAs it received were removed in the gene review.

file:interpro/panther/PTHR16431/PTHR16431-review.yaml

Family review showing PTHR16431 is the Mis18 family and fly Mastermind lacks the Mis18 domain.

Nematode LAG-3/SEL-8Molecular Functionnematode_lag3_coactivator

Annotons

LAG-3/SEL-8

lag3_coactivator

Participant: Gene Product: sel-8/lag-3 (worm)

Gene Product:

sel-8/lag-3 (worm)UniProtKB:Q09260

Function

transcription coactivator activityGO:0003713

Locations

nucleusGO:0005634

Forms the ternary complex with LAG-1 and the LIN-12 or GLP-1 intracellular domain; assigned to the Mastermind role by function rather than sequence similarity.

Part: default CSL repression (ligand-off state) (optional)

Corepressor-bound CSL in the absence of NICDRegulatory Stepcsl_default_repression

Without NICD, CSL recruits lineage-specific corepressor adaptors and HDAC/CtBP/Groucho machinery. NICD competes with these adaptors for CSL. General default repression is not established in the C. elegans germline.

Variant set: CSL corepressor adaptor by taxon / corepressor family (One Or More)

Union: vertebrates use several corepressor adaptors (SPEN/SHARP, KyoT2/FHL1, L3MBTL3), insects use Hairless; Hairless has no vertebrate ortholog.

Insect HairlessMolecular Functionhairless_corepressor

Annotons

Hairless

hairless_adaptor

Participant: Gene Product: H (fly)

Gene Product:

H (fly)UniProtKB:Q02308

Function

transcription corepressor activityGO:0003714

Processes

negative regulation of Notch signaling pathwayGO:0045746

Locations

nucleusGO:0005634

Binds the Su(H) C-terminal domain and recruits Groucho and dCtBP.

Vertebrate SPEN/SHARPMolecular Functionspen_corepressor

Annotons

SPEN/SHARP

spen_adaptor

Participant: Gene Product: SPEN (human)

Gene Product:

SPEN (human)UniProtKB:Q96T58

Function

transcription corepressor activityGO:0003714

Locations

nucleusGO:0005634

RBPJ-binding corepressor adaptor that recruits HDAC complexes.

Part 6: primary transcriptional output

Notch target gene outputRegulatory Stepnotch_target_output

The most conserved direct targets encode HES/E(spl) and HEY bHLH-Orange transcriptional repressors, which mediate lateral inhibition, progenitor maintenance, boundary formation and oscillation. Other direct targets vary by cell type.

Variant set: Direct target class by target family / lineage (One Or More)

Union: a single cell can induce HES/E(spl) and HEY genes together; the C. elegans germline instead uses lst-1 and sygl-1, which are not bHLH factors.

HES/E(spl) bHLH repressorsMolecular Functionhes_espl_output

Annotons

HES/E(spl) repressor

hes_repressor

Participant: Family: HES/E(spl) bHLH-Orange repressors

Family:

HES/E(spl) bHLH-Orange repressorsPANTHER:PTHR10985

Representative Members: HES1 (human)UniProtKB:Q14469 Hes7 (mouse)UniProtKB:Q8BKT2 her1 (zebrafish)UniProtKB:Q90463 E(spl)m8-HLH (fly)UniProtKB:P13098

Function

DNA-binding transcription repressor activity, RNA polymerase II-specificGO:0001227

Targets: N-box / class C E-box elements

Processes

Notch signaling pathwayGO:0007219

Locations

nucleusGO:0005634

WRPW/Groucho-recruiting repressors of proneural and lineage genes; Hes7/her1 drive the segmentation clock.

HEY bHLH repressorsMolecular Functionhey_output

Annotons

HEY repressor

hey_repressor

Participant: Family: HEY bHLH-Orange repressors

Family:

HEY bHLH-Orange repressorsPANTHER:PTHR10985:SF78

Representative Members: HEY1 (human)UniProtKB:Q9Y5J3

Function

DNA-binding transcription repressor activity, RNA polymerase II-specificGO:0001227

Processes

Notch signaling pathwayGO:0007219

Locations

nucleusGO:0005634

Context-dependent (vascular, cardiac, somitic) Notch targets.

Nematode germline stem-cell targetsModulenematode_germline_output

Annotons

LST-1

lst1_target

Participant: Gene Product: lst-1 (worm)

Gene Product:

lst-1 (worm)UniProtKB:P91820

Locations

cytoplasmGO:0005737

With sygl-1, one of only two primary GLP-1/LAG-1 targets in the germline stem-cell niche; acts with FBF RNA-binding proteins rather than as a transcription factor.

file:genes/worm/glp-1/glp-1-ai-review.yaml

Gene review notes lst-1 and sygl-1 as the only primary germline GLP-1 targets (PMID:32196486).