EGFR signaling pathway module

Bilaterian EGFR signaling couples an EGF-family ligand to an EGFR/ERBB-family receptor tyrosine kinase, creates phosphotyrosine docking sites for GRB2/drk/Sem-5 adaptors and SOS Ras GEFs, and routes the signal through Ras-RAF-MEK-ERK. The conserved invertebrate and vertebrate core is represented with fly and worm variants, while vertebrate ERBB heterodimer and PI3K branches are kept as optional extensions.

MODULE:egfr_signalingDRAFTSignaling Pathwaymodules/egfr_signaling.yaml

epidermal growth factor receptor signaling pathwayGO:0007173

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

EGFR signaling pathway Falcon module review

Falcon/Edison module review generated 2026-06-28 is linked as supporting evidence for module boundaries, conserved Bilaterian deployment, core mechanism, variation, constraints, and failure modes; open questions in that report require manual review before promotion to curated knowledge gaps.

GO:0007173

epidermal growth factor receptor signaling pathway

The module is grounded in the GO biological process term for epidermal growth factor receptor signaling pathway.

gomodel:67c10cc400009089

EGF signaling pathway (Human)

Human production GO-CAM grounding for EGF, EGFR, GRB2, and SOS1 in a direct EGF-to-EGFR-to-GRB2/SOS pathway.

gomodel:60ad85f700001873

epidermal growth factor receptor signaling pathway via spi-Egfr (D.mel)

Drosophila production GO-CAM grounding for the conserved Spi/Egfr/drk/Sos/ Ras85D/Raf/Dsor1/rolled route to Ras-MAPK output.

PANTHER:PTN000698827

PAINT node PTN000698827 for EGFR-family signaling

Local PAINT IBD node in PTHR24416 with Bilaterian seeds including human EGFR, Drosophila Egfr, and C. elegans let-23 for P:GO:0007173 and related EGFR pathway terms; PAINT date 20240924.

PANTHER:PTN001230349

PAINT node PTN001230349 for receptor tyrosine kinase activity

Local PAINT IBD node in PTHR24416 with propagated terms including F:GO:0004714 and P:GO:0007169 for metazoan receptor tyrosine kinases; PAINT date 20260828.

PANTHER:PTN005273574

PAINT node PTN005273574 for GRB2/drk/Sem-5 adaptors

Local PAINT IBD node in PTHR46037 with plasma-membrane recruitment, phosphotyrosine binding, EGFR binding, and signal-transduction rows that together ground the GRB2/drk/Sem-5 adaptor tier.

PANTHER:PTN008302071

PAINT node PTN008302071 for PIK3R1

Local PAINT IBD node in PTHR10155 with propagated terms for the phosphatidylinositol 3-kinase complex; PAINT date 20240516.

The module is intentionally centered on the conserved Bilaterian EGFR -> GRB2/SOS -> Ras/MAPK path. Human EGF/EGFR, Drosophila Spi/Egfr, and C. elegans LIN-3/LET-23 are alternative receptor-layer realizations, whereas the SH2/SH3 adaptor, Ras GEF, Ras, RAF, MEK, and ERK tiers are represented as broad families with human, fly, and worm exemplars. Vertebrate ERBB2 heterodimerization and PI3K signaling remain optional elaborations rather than requirements for fly or worm EGFR signaling. The Ras/MAPK tier is the same biological sidecar detailed in MODULE:erk_cascade but is embedded here because fly and worm GO-CAM support model RAF, MEK, and ERK inside EGFR signaling. PLCG, STAT, CBL, and receptor-downregulation branches are outside this compact conserved-core module.

18Nodes

14Parts

1Variant Sets

3Variants

16Annotons

10Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

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

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

5 conformance issue(s):

egfr_adaptor_gef_coupling → phosphotyrosine_adaptor_recruitment [info]
tier count 4 does not match template 3 (phosphotyrosine_adaptor_recruitment)
egfr_adaptor_gef_coupling → phosphotyrosine_adaptor_recruitment [info]
tier 1 function None does not match template None
egfr_adaptor_gef_coupling → phosphotyrosine_adaptor_recruitment [info]
connection topology does not match the template motif
egfr_ras_switch → gtpase_switch [info]
tier count 2 does not match template 3 (gtpase_switch)
egfr_ras_switch → gtpase_switch [info]
connection topology does not match the template motif

Function consistency and core coverage

25 gene-function check(s) reflected in core functions · 0 conflict(s) · 12 evidence or coverage gap(s) (37 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
human_egf_ligand	EGF UniProtKB:P01133 Gene	growth factor activity GO:0008083	Annotation Supported A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
human_egfr_receptor	EGFR UniProtKB:P00533 Gene	epidermal growth factor receptor activity GO:0005006	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fly_spitz_ligand	spi UniProtKB:Q01083 Gene	receptor ligand activity GO:0048018	Annotation Supported A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
fly_egfr_receptor	Egfr UniProtKB:P04412 Gene	epidermal growth factor receptor activity GO:0005006	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
worm_lin3_ligand	LIN-3 UniProtKB:Q03345 Gene	receptor ligand activity GO:0048018	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
worm_let23_receptor	LET-23 UniProtKB:P24348 Gene	epidermal growth factor receptor activity GO:0005006	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erbb2_coreceptor_kinase	ERBB2 UniProtKB:P04626 Gene	transmembrane receptor protein tyrosine kinase activity GO:0004714	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
grb2_drk_sem5_adaptor	GRB2 UniProtKB:P62993 Family Representative	phosphotyrosine residue binding GO:0001784	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
grb2_drk_sem5_adaptor	drk (Drosophila) UniProtKB:Q08012 Family Representative	phosphotyrosine residue binding GO:0001784	Annotation Supported A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
grb2_drk_sem5_adaptor	sem-5 (C. elegans) UniProtKB:P29355 Family Representative	phosphotyrosine residue binding GO:0001784	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
grb2_drk_sem5_sos_adaptor	GRB2 UniProtKB:P62993 Family Representative	protein-macromolecule adaptor activity GO:0030674	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
grb2_drk_sem5_sos_adaptor	drk (Drosophila) UniProtKB:Q08012 Family Representative	protein-macromolecule adaptor activity GO:0030674	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
grb2_drk_sem5_sos_adaptor	sem-5 (C. elegans) UniProtKB:P29355 Family Representative	protein-macromolecule adaptor activity GO:0030674	Function Unreviewed No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
sos_ras_gef	SOS1 UniProtKB:Q07889 Family Representative	guanyl-nucleotide exchange factor activity GO:0005085	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sos_ras_gef	Sos (Drosophila) UniProtKB:P26675 Family Representative	guanyl-nucleotide exchange factor activity GO:0005085	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sos_ras_gef	sos-1 (C. elegans) UniProtKB:Q9N5D3 Family Representative	guanyl-nucleotide exchange factor activity GO:0005085	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ras_switch	KRAS UniProtKB:P01116 Family Representative	GTPase activity GO:0003924	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ras_switch	Ras85D (Drosophila) UniProtKB:P08646 Family Representative	GTPase activity GO:0003924	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ras_switch	let-60 (C. elegans) UniProtKB:P22981 Family Representative	GTPase activity GO:0003924	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
raf_map3k	BRAF UniProtKB:P15056 Family Representative	MAP kinase kinase kinase activity GO:0004709	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
raf_map3k	Raf (Drosophila) UniProtKB:P11346 Family Representative	MAP kinase kinase kinase activity GO:0004709	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
raf_map3k	lin-45 (C. elegans) UniProtKB:Q07292 Family Representative	MAP kinase kinase kinase activity GO:0004709	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mek_map2k	MAP2K1 UniProtKB:Q02750 Family Representative	MAP kinase kinase activity GO:0004708	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mek_map2k	Dsor1 (Drosophila) UniProtKB:Q24324 Family Representative	MAP kinase kinase activity GO:0004708	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mek_map2k	mek-2 (C. elegans) UniProtKB:Q10664 Family Representative	MAP kinase kinase activity GO:0004708	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erk_mapk	MAPK1 UniProtKB:P28482 Family Representative	MAP kinase activity GO:0004707	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erk_mapk	rl (Drosophila) UniProtKB:P40417 Family Representative	MAP kinase activity GO:0004707	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erk_mapk	mpk-1 (C. elegans) UniProtKB:P39745 Family Representative	MAP kinase activity GO:0004707	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pik3r1_pi3k_p85_adaptor	PIK3R1 UniProtKB:P27986 Family Representative	1-phosphatidylinositol-3-kinase regulator activity GO:0046935	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
grb2_drk_sem5_adaptor	GRB2/drk/Sem-5 SH2-SH3 adaptors PANTHER:PTHR46037 Family	phosphotyrosine residue binding GO:0001784	Family Review Missing No supported structured family review is available for PANTHER:PTHR46037.
grb2_drk_sem5_sos_adaptor	GRB2/drk/Sem-5 SH2-SH3 adaptors PANTHER:PTHR46037 Family	protein-macromolecule adaptor activity GO:0030674	Family Review Missing No supported structured family review is available for PANTHER:PTHR46037.
sos_ras_gef	SOS Ras guanine nucleotide exchange factors Family	guanyl-nucleotide exchange factor activity GO:0005085	Family Id Missing The family has no identifier linking it to a curated family review.
ras_switch	Ras GTPases Family	GTPase activity GO:0003924	Family Id Missing The family has no identifier linking it to a curated family review.
raf_map3k	RAF-family MAP kinase kinase kinases Family	MAP kinase kinase kinase activity GO:0004709	Family Id Missing The family has no identifier linking it to a curated family review.
mek_map2k	MEK-family MAP kinase kinases Family	MAP kinase kinase activity GO:0004708	Family Id Missing The family has no identifier linking it to a curated family review.
erk_mapk	ERK-family MAP kinases Family	MAP kinase activity GO:0004707	Family Id Missing The family has no identifier linking it to a curated family review.
pik3r1_pi3k_p85_adaptor	PI3K p85 regulatory adaptors PANTHER:PTHR10155 Family	1-phosphatidylinositol-3-kinase regulator activity GO:0046935	Family Review Missing No supported structured family review is available for PANTHER:PTHR10155.

Gene-review completeness (26/26 grounded genes reviewed)

11 complete review(s) · 23 with deep research · 0 missing review · 3 reviewed but lacking deep research

Gene	Review	Complete	Deep research
BRAF P15056	✓	277/278	✓
drk Q08012	✓	74/76	✓
Dsor1 Q24324	✓	✓	✓
EGF P01133	✓	230/234	✗
EGFR P00533	✓	967/1008	✓
Egfr P04412	✓	137/141	✓
ERBB2 P04626	✓	✓	✗
GRB2 P62993	✓	✓	✓
KRAS P01116	✓	✓	✓
let-23 P24348	✓	39/40	✓
let-60 P22981	✓	40/45	✓
lin-3 Q03345	✓	24/26	✓
lin-45 Q07292	✓	✓	✓
MAP2K1 Q02750	✓	191/193	✓
MAPK1 P28482	✓	✓	✓
mek-2 Q10664	✓	✓	✓
mpk-1 P39745	✓	✓	✓
PIK3R1 P27986	✓	413/415	✓
Raf P11346	✓	89/90	✓
Ras85D P08646	✓	✓	✓
rl P40417	✓	119/125	✓
sem-5 P29355	✓	✓	✓
Sos P26675	✓	47/50	✗
sos-1 Q9N5D3	✓	11/12	✓
SOS1 Q07889	✓	✓	✓
spi Q01083	✓	63/65	✓

Tree

EGFR signaling pathwaySignaling Pathwayegfr_signaling

Parts
1. 1. ligand-dependent EGFR-family receptor activation
2. EGF-family ligand activates an EGFR-family RTKRegulatory Stepegfr_receptor_activation
  
  Variants
  1. Ligand/receptor realization by species and receptor-family deployment (One Or More)
    
    Human EGF/EGFR activationRegulatory Stephuman_egf_egfr_activation
    
    Annotons
    
    EGF ligand Gene Product: EGF
    
    EGFR receptor kinase Gene Product: EGFR
    
    Drosophila Spi/Egfr activationRegulatory Stepfly_spi_egfr_activation
    
    Annotons
    
    Spitz ligand Gene Product: spi
    
    Egfr receptor kinase Gene Product: Egfr
    
    C. elegans LIN-3/LET-23 activationRegulatory Stepworm_lin3_let23_activation
    
    Annotons
    
    LIN-3 ligand Gene Product: LIN-3
    
    LET-23 receptor kinase Gene Product: LET-23
3. 2. vertebrate ERBB2 co-receptor branch optional
4. Vertebrate ERBB2 co-receptor amplificationRegulatory Stepvertebrate_erbb2_coreceptor_branch
  
  Annotons
  - ERBB2 co-receptor kinase Gene Product: ERBB2
5. 3. GRB2/SOS coupling to Ras
6. GRB2/drk/Sem-5 recruits SOS and activates RasRegulatory Stepegfr_adaptor_gef_coupling
  
  Parts
  1. 1. receptor phosphotyrosine docking site
  2. Activated EGFR-family phosphotyrosine docking siteRegulatory Stepegfr_phosphotyrosine_site
    
    Annotons
    
    activated EGFR-family phosphotyrosine site Family: activated EGFR-family receptors
  3. 2. GRB2 phosphotyrosine binding
  4. GRB2/drk/Sem-5 binding to receptor phosphotyrosinesReactiongrb2_phosphotyrosine_binding
    
    Annotons
    
    GRB2/drk/Sem-5 phosphotyrosine binding Family: GRB2/drk/Sem-5 SH2-SH3 adaptors
  5. 3. adaptor-mediated SOS recruitment
  6. GRB2/drk/Sem-5 recruitment of SOSRegulatory Stepgrb2_sos_recruitment
    
    Annotons
    
    GRB2/drk/Sem-5 SOS adaptor Family: GRB2/drk/Sem-5 SH2-SH3 adaptors
  7. 4. Ras nucleotide switch
  8. SOS-loaded Ras GTPase switchReactionegfr_ras_switch
    
    Parts
    
    1. SOS GEF tier
    
    SOS guanine nucleotide exchange on RasReactionsos_gef_step
    
    Annotons
    
    SOS Ras GEF Family: SOS Ras guanine nucleotide exchange factors
    
    2. active Ras GTPase tier
    
    Active Ras GTPaseReactionras_active_step
    
    Annotons
    
    Ras GTPase switch Family: Ras GTPases
7. 4. RAF-MEK-ERK output
8. RAF-MEK-ERK relay downstream of EGFR-activated RasSignaling Pathwayegfr_ras_erk_output
  
  Parts
  1. 1. RAF MAP3K tier
  2. RAF MAP kinase kinase kinase activationReactionegfr_raf_map3k_tier
    
    Annotons
    
    RAF MAP3K Family: RAF-family MAP kinase kinase kinases
  3. 2. MEK MAP2K tier
  4. MEK MAP kinase kinase activationReactionegfr_mek_map2k_tier
    
    Annotons
    
    MEK MAP2K Family: MEK-family MAP kinase kinases
  5. 3. ERK MAPK tier
  6. ERK MAP kinase activationReactionegfr_erk_mapk_tier
    
    Annotons
    
    ERK MAPK Family: ERK-family MAP kinases
9. 5. vertebrate PI3K extension optional
10. Vertebrate ERBB-to-PI3K branchSignaling Pathwayvertebrate_pi3k_branch
  
  Annotons
  - PI3K p85 adaptor Family: PI3K p85 regulatory adaptors

Details

Context

bilateriansNCBITaxon:33213

plasma membraneGO:0005886 cytosolGO:0005829 nucleusGO:0005634

EGFR signaling pathwaySignaling Pathwayegfr_signaling

epidermal growth factor receptor signaling pathwayGO:0007173

Context

bilateriansNCBITaxon:33213

plasma membraneGO:0005886 cytosolGO:0005829 nucleusGO:0005634

Connections

egfr_receptor_activation -> egfr_adaptor_gef_coupling Causes

Ligand-dependent EGFR-family receptor activation creates phosphotyrosine docking sites that recruit GRB2/drk/Sem-5 and SOS.

egfr_adaptor_gef_coupling -> egfr_ras_erk_output Causes

Receptor-recruited SOS activates Ras and thereby initiates the RAF-MEK-ERK relay.

egfr_receptor_activation -> vertebrate_erbb2_coreceptor_branch Causes

Ligand-bound vertebrate EGFR-family receptors can recruit ERBB2 as an optional kinase-active co-receptor.

egfr_receptor_activation -> vertebrate_pi3k_branch Causes

Vertebrate EGFR-family receptor complexes can recruit PI3K p85 adaptors as an extension of the conserved EGFR core.

Part 1: ligand-dependent EGFR-family receptor activation

EGF-family ligand activates an EGFR-family RTKRegulatory Stepegfr_receptor_activation

A secreted or membrane-tethered EGF-family ligand binds an EGFR-family receptor and promotes formation of an active receptor tyrosine kinase signaling complex at the plasma membrane.

Variant set: Ligand/receptor realization by species and receptor-family deployment (One Or More)

Human EGF/EGFR activationRegulatory Stephuman_egf_egfr_activation

EGF binding to human EGFR/ERBB1 initiates canonical EGFR signaling.

Context

humanNCBITaxon:9606

Annotons

EGF ligand

human_egf_ligand

Participant: Gene Product: EGF

Gene Product:

EGFUniProtKB:P01133

Function

growth factor activityGO:0008083

Processes

epidermal growth factor receptor signaling pathwayGO:0007173

Human EGF ligand that provides the extracellular input.

EGFR receptor kinase

human_egfr_receptor

Participant: Gene Product: EGFR

Gene Product:

EGFRUniProtKB:P00533

Function

epidermal growth factor receptor activityGO:0005006

Processes

epidermal growth factor receptor signaling pathwayGO:0007173

Ligand-activated receptor kinase and phosphotyrosine scaffold.

Drosophila Spi/Egfr activationRegulatory Stepfly_spi_egfr_activation

Spitz activates Drosophila Egfr/DER/Torpedo, a single fly EGFR-family receptor that feeds the conserved drk-Sos-Ras85D-MAPK chain.

Context

Drosophila melanogasterNCBITaxon:7227

Annotons

Spitz ligand

fly_spitz_ligand

Participant: Gene Product: spi

Gene Product:

spiUniProtKB:Q01083

Function

receptor ligand activityGO:0048018

Drosophila EGF-family ligand exemplar.

Egfr receptor kinase

fly_egfr_receptor

Participant: Gene Product: Egfr

Gene Product:

EgfrUniProtKB:P04412

Function

epidermal growth factor receptor activityGO:0005006

Processes

epidermal growth factor receptor signaling pathwayGO:0007173

Drosophila EGFR/DER receptor tyrosine kinase.

C. elegans LIN-3/LET-23 activationRegulatory Stepworm_lin3_let23_activation

LIN-3 activates the single worm EGFR-family receptor LET-23, coupling vulval-induction and related developmental signals to the conserved SEM-5/SOS-1/LET-60/LIN-45/MEK-2/MPK-1 cascade.

Context

C. elegansNCBITaxon:6239

Annotons

LIN-3 ligand

worm_lin3_ligand

Participant: Gene Product: LIN-3

Gene Product:

LIN-3UniProtKB:Q03345

Function

receptor ligand activityGO:0048018

C. elegans EGF-family ligand exemplar.

LET-23 receptor kinase

worm_let23_receptor

Participant: Gene Product: LET-23

Gene Product:

LET-23UniProtKB:P24348

Function

epidermal growth factor receptor activityGO:0005006

Processes

epidermal growth factor receptor signaling pathwayGO:0007173

C. elegans LET-23 EGFR-family receptor tyrosine kinase.

Part 2: vertebrate ERBB2 co-receptor branch (optional)

Vertebrate ERBB2 co-receptor amplificationRegulatory Stepvertebrate_erbb2_coreceptor_branch

Ligand-bound vertebrate EGFR-family receptors can recruit ligandless ERBB2 as a kinase-active dimerization partner that amplifies RTK output.

Context

vertebratesNCBITaxon:7742

Annotons

ERBB2 co-receptor kinase

erbb2_coreceptor_kinase

Participant: Gene Product: ERBB2

Gene Product:

ERBB2UniProtKB:P04626

Function

transmembrane receptor protein tyrosine kinase activityGO:0004714

Vertebrate ERBB dimerization partner that amplifies RTK output.

Part 3: GRB2/SOS coupling to Ras

GRB2/drk/Sem-5 recruits SOS and activates RasRegulatory Stepegfr_adaptor_gef_coupling

SH2/SH3 adaptors bind activated EGFR-family receptor phosphotyrosines and recruit SOS-family Ras GEFs that load GTP onto Ras.

Connections

egfr_phosphotyrosine_site -> grb2_phosphotyrosine_binding Provides Input For

EGFR-family receptor phosphotyrosines are recognized by GRB2/drk/Sem-5.

grb2_phosphotyrosine_binding -> grb2_sos_recruitment Causes

Docked GRB2/drk/Sem-5 recruits SOS-family Ras GEFs.

grb2_sos_recruitment -> egfr_ras_switch Causes

GRB2-recruited SOS catalyzes Ras GTP loading.

Part 1: receptor phosphotyrosine docking site

Activated EGFR-family phosphotyrosine docking siteRegulatory Stepegfr_phosphotyrosine_site

Ligand-activated EGFR-family receptor kinases provide phosphotyrosine docking sites for SH2-domain adaptors.

Annotons

activated EGFR-family phosphotyrosine site

activated_egfr_phosphotyrosine_site

Participant: Family: activated EGFR-family receptors

Family:

activated EGFR-family receptors

Representative Members: EGFRUniProtKB:P00533 Egfr (Drosophila)UniProtKB:P04412 let-23 (C. elegans)UniProtKB:P24348

Activated receptor phosphotyrosine motifs that dock the GRB2/drk/Sem-5 SH2 domain.

Part 2: GRB2 phosphotyrosine binding

GRB2/drk/Sem-5 binding to receptor phosphotyrosinesReactiongrb2_phosphotyrosine_binding

The GRB2/drk/Sem-5 SH2 domain binds phosphorylated EGFR-family receptor tails at the membrane.

Annotons

GRB2/drk/Sem-5 phosphotyrosine binding

grb2_drk_sem5_adaptor

Participant: Family: GRB2/drk/Sem-5 SH2-SH3 adaptors

Family:

GRB2/drk/Sem-5 SH2-SH3 adaptorsPANTHER:PTHR46037

Representative Members: GRB2UniProtKB:P62993 drk (Drosophila)UniProtKB:Q08012 sem-5 (C. elegans)UniProtKB:P29355

Function

phosphotyrosine residue bindingGO:0001784

SH2-domain reader of receptor phosphotyrosines.

Part 3: adaptor-mediated SOS recruitment

GRB2/drk/Sem-5 recruitment of SOSRegulatory Stepgrb2_sos_recruitment

GRB2/drk/Sem-5 uses its SH3 domains to recruit SOS-family Ras guanine nucleotide exchange factors to the activated receptor.

Annotons

GRB2/drk/Sem-5 SOS adaptor

grb2_drk_sem5_sos_adaptor

Participant: Family: GRB2/drk/Sem-5 SH2-SH3 adaptors

Family:

GRB2/drk/Sem-5 SH2-SH3 adaptorsPANTHER:PTHR46037

Representative Members: GRB2UniProtKB:P62993 drk (Drosophila)UniProtKB:Q08012 sem-5 (C. elegans)UniProtKB:P29355

Function

protein-macromolecule adaptor activityGO:0030674

Targets: SOS-family Ras GEF

SH3-domain adaptor that recruits SOS-family Ras GEFs.

Part 4: Ras nucleotide switch

SOS-loaded Ras GTPase switchReactionegfr_ras_switch

Membrane-recruited SOS catalyzes GDP-for-GTP exchange on Ras, producing the GTP-loaded Ras state that engages RAF-family MAP3Ks.

Connections

sos_gef_step -> ras_active_step Causes

SOS loads GTP onto Ras, activating the switch.

Part 1: SOS GEF tier

SOS guanine nucleotide exchange on RasReactionsos_gef_step

SOS-family Ras GEFs load GTP onto Ras downstream of EGFR-bound GRB2/drk/Sem-5.

Annotons

SOS Ras GEF

sos_ras_gef

Participant: Family: SOS Ras guanine nucleotide exchange factors

Family:

SOS Ras guanine nucleotide exchange factors

Representative Members: SOS1UniProtKB:Q07889 Sos (Drosophila)UniProtKB:P26675 sos-1 (C. elegans)UniProtKB:Q9N5D3

Function

guanyl-nucleotide exchange factor activityGO:0005085

Targets: Ras-family GTPase

Ras-directed guanine nucleotide exchange downstream of EGFR.

Part 2: active Ras GTPase tier

Active Ras GTPaseReactionras_active_step

GTP-loaded Ras is the binary switch state that couples recruited SOS to RAF-family MAP3Ks.

Annotons

Ras GTPase switch

ras_switch

Participant: Family: Ras GTPases

Family:

Ras GTPases

Representative Members: KRASUniProtKB:P01116 Ras85D (Drosophila)UniProtKB:P08646 let-60 (C. elegans)UniProtKB:P22981

Function

GTPase activityGO:0003924

Binary Ras switch that couples recruited SOS to RAF-family kinases.

Part 4: RAF-MEK-ERK output

RAF-MEK-ERK relay downstream of EGFR-activated RasSignaling Pathwayegfr_ras_erk_output

GTP-loaded Ras activates RAF-family MAP3Ks, which activate MEK-family MAP2Ks and ERK-family MAPKs to alter cytoplasmic and nuclear substrates.

ERK1 and ERK2 cascadeGO:0070371

Connections

egfr_raf_map3k_tier -> egfr_mek_map2k_tier Causes

RAF-family MAP3Ks phosphorylate and activate MEK-family MAP2Ks.

egfr_mek_map2k_tier -> egfr_erk_mapk_tier Causes

MEK-family MAP2Ks phosphorylate and activate ERK-family MAPKs.

Part 1: RAF MAP3K tier

RAF MAP kinase kinase kinase activationReactionegfr_raf_map3k_tier

GTP-loaded Ras activates RAF-family MAP kinase kinase kinases.

Annotons

RAF MAP3K

raf_map3k

Participant: Family: RAF-family MAP kinase kinase kinases

Family:

RAF-family MAP kinase kinase kinases

Representative Members: BRAFUniProtKB:P15056 Raf (Drosophila)UniProtKB:P11346 lin-45 (C. elegans)UniProtKB:Q07292

Function

MAP kinase kinase kinase activityGO:0004709

MAP3K tier of the ERK relay.

Part 2: MEK MAP2K tier

MEK MAP kinase kinase activationReactionegfr_mek_map2k_tier

RAF-family MAP3Ks phosphorylate and activate MEK-family MAP kinase kinases.

Annotons

MEK MAP2K

mek_map2k

Participant: Family: MEK-family MAP kinase kinases

Family:

MEK-family MAP kinase kinases

Representative Members: MAP2K1UniProtKB:Q02750 Dsor1 (Drosophila)UniProtKB:Q24324 mek-2 (C. elegans)UniProtKB:Q10664

Function

MAP kinase kinase activityGO:0004708

MAP2K tier that dually phosphorylates the ERK MAPK.

Part 3: ERK MAPK tier

ERK MAP kinase activationReactionegfr_erk_mapk_tier

MEK-family MAP2Ks dually phosphorylate ERK-family MAP kinases on their activation loops.

Annotons

ERK MAPK

erk_mapk

Participant: Family: ERK-family MAP kinases

Family:

ERK-family MAP kinases

Representative Members: MAPK1UniProtKB:P28482 rl (Drosophila)UniProtKB:P40417 mpk-1 (C. elegans)UniProtKB:P39745

Function

MAP kinase activityGO:0004707

Terminal ERK MAPK output of the conserved cascade.

Part 5: vertebrate PI3K extension (optional)

Vertebrate ERBB-to-PI3K branchSignaling Pathwayvertebrate_pi3k_branch

In vertebrates, activated ERBB-family receptor complexes can route phosphotyrosine signals to class IA PI3K regulatory adaptors in parallel with the core Ras/MAPK output.

Context

vertebratesNCBITaxon:7742

Annotons

PI3K p85 adaptor

pik3r1_pi3k_p85_adaptor

Participant: Family: PI3K p85 regulatory adaptors

Family:

PI3K p85 regulatory adaptorsPANTHER:PTHR10155

Representative Members: PIK3R1UniProtKB:P27986

Function

1-phosphatidylinositol-3-kinase regulator activityGO:0046935

SH2-containing PI3K regulatory subunit recruited to activated ERBB complexes.