ERK1/2 (Ras-RAF-MEK-ERK) MAPK cascade module

A taxon-neutral decomposition of the canonical Ras-RAF-MEK-ERK mitogen-activated protein kinase cascade, the concrete ERK1/2 realization of the generic three-tier MAP kinase relay (MODULE:mapk_relay). The cascade converts receptor-proximal tyrosine-phosphorylation events into ERK1/ERK2 activity and a proliferative/differentiation transcriptional program, and is deployed downstream of many distinct receptor systems: receptor tyrosine kinases (EGFR, FGFR, PDGFR, insulin/IGF), cytokine receptors signaling through JAKs, G-protein-coupled receptors, and integrins. The module captures six parts, numbered as in `parts`: (1) recruitment of SH2/SH3 adaptors (GRB2, SHC) to a receptor phosphotyrosine, with GRB2-mediated recruitment of the Ras guanine nucleotide exchange factor SOS; (2) the Ras nucleotide switch (SOS GEF -> Ras GTPase -> RasGAP), declared as an inner bundle that `conforms_to` gtpase_switch; (3) the conforming ERK kinase relay - Ras-driven RAF(MAP3K) -> MEK1/2(MAP2K) -> ERK1/2(MAPK) on the TEY motif - declared as an inner bundle that `conforms_to` mapk_relay; (4) ERK action on nuclear (ELK1/Ets, RSK, MSK) and cytoplasmic substrates to drive transcription, proliferation, and differentiation; (5) DUSP/MKP negative feedback on ERK; and (6) optional Sprouty/SPRED feedback inhibition at the SOS-Ras-RAF level. Grounded in GO:0000165 (MAPK cascade) / GO:0070371 (ERK1 and ERK2 cascade).

MODULE:erk_cascadeDRAFTSignaling Pathwaymodules/erk_cascade.yaml
MAPK cascadeGO:0000165 ERK1 and ERK2 cascadeGO:0070371
GO:0000165
MAPK cascade
The module is grounded in the GO biological process term for the MAPK cascade, an intracellular protein kinase cascade containing at least a MAPK, a MAP2K, and a MAP3K acting in series.
GO:0070371
ERK1 and ERK2 cascade
The terminal tier of this module is the ERK1/ERK2 cascade, the classical mitogen-responsive MAPK module.
GO:0007265
Ras protein signal transduction
The switch tier is grounded in Ras protein signal transduction: GTP-bound Ras transmits the signal from receptor-recruited GEFs to the RAF kinases.
PANTHER:PTN000631348
PAINT Ras GTPase ancestral node
Local PAINT IBD seed rows place curated HRAS/KRAS/NRAS exemplars in PTHR24070 node PTN000631348 with GTPase activity and small GTPase-mediated signal-transduction terms.
PANTHER:PTN008604616
PAINT Ras protein signal transduction node
Local PAINT IBD seed rows place curated HRAS/KRAS/NRAS exemplars in a Ras protein signal transduction node, anchoring the Ras-switch tier evolutionarily where the cache supports it.

This module is the concrete ERK1/2 branch of the generic three-tier MAP kinase relay (MODULE:mapk_relay), and embeds two nested conforming bundles: the inner `erk_relay` node bundles the RAF -> MEK -> ERK tiers and conforms to mapk_relay, and the inner `ras_nucleotide_switch` node bundles the SOS GEF -> Ras GTPase -> RasGAP tiers and conforms to MODULE:gtpase_switch. The receptor- proximal adaptor step and the downstream ERK-output and DUSP-feedback steps are this cascade's free extensions around the conforming cores. The module is intentionally a reusable "sidecar": it is deployed downstream of many receptor systems rather than being specific to one. It is referenced as a branch-point interface by the JAK-STAT signaling module (MODULE:jak_stat_signaling), where JAK-phosphorylated receptor tyrosines recruit GRB2/SHC and fork into this cascade in parallel with STAT activation; ERK in turn feeds back onto STATs via C-terminal serine phosphorylation. The same module is deployed by RTKs, GPCRs (often via PI3K/PKC or transactivation), and integrins. Representative UniProt members were verified against curated reviews in this repository; tiers without a verified local exemplar are given as family descriptors with preferred_term and description. PANTHER grounding: kinase-tier family descriptors carry family-level PTHR ids checked against interpro/panther membership (PTHR24055 for every MAPK tier, PTHR48013 for all MAP2Ks, including MEK1/MEK2, MKK3/4/5/6/7 and Pbs2/Ste7, per the current PANTHER classification, PTHR24361 for MEKK2/MEKK3). PANTHER subfamilies are deliberately not used: they are not clean paralog groups here (e.g. PTHR48013:SF9, named for MEK5, also contains yeast Ste7 and plant MKKs), so branch identity is carried by the representative members and the PTN evidence rather than by a subfamily id. The RAF family id PTHR44329 carries PANTHER's official name (TNNI3K-related) but contains BRAF, RAF1 and ARAF. The GRB2/SHC adaptor and DUSP descriptors mix unrelated PANTHER families and assert no id; the MAP3K tiers of the stress cascades likewise stay id-free.

16Nodes
12Parts
1Variant Sets
3Variants
13Annotons
15Connections

Executable models all models

Boolean derived from this module
ERK cascade as a Boolean network
✓ No stimulus (fixed point)
✓ Sustained stimulus (cyclic)
✓ Feedback loops cut (fixed point)
✓ DUSP and Sprouty knocked out (cyclic)
✓ MEK inhibited (fixed point)
✓ RasGAP active (fixed point)
Run in browser →
Boolean external
MAPK network and cancer cell fate decisions (Grieco 2013)
model.bnet · mapping_to_modules.yaml

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

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

Leaf nodes lacking representative members

1 leaf node(s) with no concrete protein grounding:

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

19 gene-function check(s) reflected in core functions · 0 conflict(s) · 14 evidence or coverage gap(s) (34 comparison(s))

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

AnnotonParticipantFunctionAssessment
sos_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).
ras_gtpase 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_gtpase HRAS
UniProtKB:P01112
Family Representative 		GTPase activity
GO:0003924 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ras_gtpase NRAS
UniProtKB:P01111
Family Representative 		GTPase activity
GO:0003924 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rasgap_role NF1 (neurofibromin)
UniProtKB:P21359
Family Representative 		GTPase activator activity
GO:0005096 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rasgap_role RASA1 (p120RasGAP)
UniProtKB:P20936
Family Representative 		GTPase activator activity
GO:0005096 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
raf_kinase 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_kinase RAF1 (CRAF)
UniProtKB:P04049
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_kinase MEK1 (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_kinase MEK2 (MAP2K2)
UniProtKB:P36507
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_kinase ERK2 (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_kinase ERK1 (MAPK3)
UniProtKB:P27361
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_substrate_output ANY_WITH_FUNCTION
Gene 		MAP kinase activity
GO:0004707 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
rsk_kinase RPS6KA1 (RSK1)
UniProtKB:Q15418
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
rsk_kinase RPS6KA3 (RSK2)
UniProtKB:P51812
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
dusp_role DUSP6
UniProtKB:Q16828
Family Representative 		MAP kinase tyrosine/serine/threonine phosphatase activity
GO:0017017 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
spry_grb2_sequestration SPRY2
UniProtKB:O43597
Family Representative 		protein sequestering activity
GO:0140311 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
spry_raf_inhibition SPRY1
UniProtKB:O43609
Family Representative 		protein kinase inhibitor activity
GO:0004860 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
spry_raf_inhibition SPRY2
UniProtKB:O43597
Family Representative 		protein kinase inhibitor activity
GO:0004860 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
spry_raf_inhibition SPRY4
UniProtKB:Q9C004
Family Representative 		protein kinase inhibitor activity
GO:0004860 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
spred_nf1_recruitment SPRED1
UniProtKB:Q7Z699
Family Representative 		protein-membrane adaptor activity
GO:0043495 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
spred_nf1_recruitment SPRED2
UniProtKB:Q7Z698
Family Representative 		protein-membrane adaptor activity
GO:0043495 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
grb2_shc_adaptor GRB2/SHC adaptor proteins
Family 		phosphotyrosine residue binding
GO:0001784 		Family Id Missing
The family has no identifier linking it to a curated family review.
sos_gef SOS Ras GEFs
PANTHER:PTHR23113
Family 		guanyl-nucleotide exchange factor activity
GO:0005085 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR23113.
ras_gtpase Ras GTPases (HRAS/KRAS/NRAS)
PANTHER:PTHR24070
Family 		GTPase activity
GO:0003924 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24070.
rasgap_role RasGAPs (e.g. NF1, RASA1)
PANTHER:PTHR10194
Family 		GTPase activator activity
GO:0005096 		Family Function Unreviewed
Family review leaves GO:0005096 UNRESOLVED. Neurofibromin and p120GAP mutagenesis directly establish Ras GTPase activation through a catalytic interface that positions the arginine-finger region. The mosquito RasGAP domain and conserved-site signature support a comparable GAP mechanism. Ras versus Rap preference and inactive interface variants require branch-specific analysis; the complete functional set is not restricted to the benchmark Raskol subfamily.
raf_kinase RAF kinases
PANTHER:PTHR44329
Family 		MAP kinase kinase kinase activity
GO:0004709 		Family Function Unreviewed
Family review leaves GO:0004674 UNRESOLVED. True for most characterized lineages: RAF, MLK/MAP3K, MOS, RIPK1-3 and CTR1. It is not safe family-wide, because it fails for the pseudokinase lineages (ILK, MLKL, pTKL). (The Dictyostelium STAT kinases Pyk3, for which serine/threonine activity is negligible, and DrkA are PTHR23257 leaves in PANTHER 19 and do not bear on this family.) Listing every serine/threonine subfamily of a 136-subfamily family is beyond this review, so the term is left unresolved rather than given a partial SUBFAMILY_ONLY list. Gene-level review should decide it per member.
mek_kinase MEK1/MEK2 (MAP2K1/MAP2K2)
PANTHER:PTHR48013
Family 		MAP kinase kinase activity
GO:0004708 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR48013.
erk_kinase ERK1/ERK2 (MAPK3/MAPK1)
PANTHER:PTHR24055
Family 		MAP kinase activity
GO:0004707 		Family Function Unreviewed
Family review leaves GO:0004707 UNRESOLVED. The cucumber target has a MAP-kinase conserved-site signature, supporting MAPK-type phosphotransfer rather than an arbitrary kinase label. Classical MAPKs and divergent CMGC relatives nevertheless differ in activation-loop regulation and upstream kinases. The complete functional boundary cannot be inferred from a rule-generated catalytic equation or extended to every CMGC-like member without catalytic and activation-mechanism evidence.
rsk_kinase RSK (p90 ribosomal S6 kinases, RPS6KA1-3/6)
Family 		protein serine/threonine kinase activity
GO:0004674 		Family Id Missing
The family has no identifier linking it to a curated family review.
dusp_role DUSP/MKP dual-specificity phosphatases
PANTHER:PTHR10159
Family 		MAP kinase tyrosine/serine/threonine phosphatase activity
GO:0017017 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10159.
spry_grb2_sequestration SPRY2 orthologs
PANTHER:PTHR12365:SF8
Family 		protein sequestering activity
GO:0140311 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR12365:SF8.
spry_raf_inhibition Sprouty paralogs
PANTHER:PTHR12365
Family 		protein kinase inhibitor activity
GO:0004860 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR12365.
spred_nf1_recruitment SPRED paralogs
PANTHER:PTHR11202
Family 		protein-membrane adaptor activity
GO:0043495 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11202.

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.

  • mapk_negative_regulation ⊣ erk_mapk [closed]
    mapk_negative_regulation is regulated by erk_output: feedback loop closed
  • sprouty_spred_feedback ⊣ ras_nucleotide_switch [closed]
    sprouty_spred_feedback is regulated by erk_output: feedback loop closed
  • erk_mapk ⊣ raf_map3k [closed]
    erk_mapk is regulated by mek_map2k: feedback loop closed
  • erk_output ⊣ ras_gef_step [closed]
    erk_output is regulated by erk_relay: feedback loop closed
  • rasgap_step ⊣ ras_active [input]
    rasgap_step is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (18/20 grounded genes reviewed)

8 complete review(s) · 17 with deep research · 2 missing review · 1 reviewed but lacking deep research

Gene Review Complete Deep research
BRAF P15056 ✓ 277/278 ✓
DUSP6 Q16828 ✓ ✓ ✓
HRAS P01112 ✓ ✓ ✓
KRAS P01116 ✓ ✓ ✓
MAP2K1 Q02750 ✓ 191/193 ✓
MAP2K2 P36507 ✓ 159/174 ✓
MAPK1 P28482 ✓ ✓ ✓
MAPK3 P27361 ✓ 244/247 ✓
NF1 P21359 ✓ ✓ ✓
NRAS P01111 ✓ ✓ ✗
RPS6KA3 (RSK2) P51812 ✗ — —
RPS6KA1 (RSK1) Q15418 ✗ — —
RAF1 P04049 ✓ 351/352 ✓
RASA1 P20936 ✓ 67/68 ✓
SOS1 Q07889 ✓ ✓ ✓
SPRED1 Q7Z699 ✓ 502/506 ✓
SPRED2 Q7Z698 ✓ 87/89 ✓
SPRY1 O43609 ✓ 113/114 ✓
SPRY2 O43597 ✓ 139/140 ✓
SPRY4 Q9C004 ✓ ✓ ✓

Details

Context
metazoaNCBITaxon:33208
cytosolGO:0005829 plasma membraneGO:0005886 nucleusGO:0005634
ERK1/2 (Ras-RAF-MEK-ERK) cascadeSignaling Pathwayerk_cascade
MAPK cascadeGO:0000165 ERK1 and ERK2 cascadeGO:0070371
Context
metazoaNCBITaxon:33208
cytosolGO:0005829 plasma membraneGO:0005886 nucleusGO:0005634

Connections

Adaptors recruit the Ras GEF SOS to the membrane.
GTP-Ras recruits and activates the RAF tier of the ERK relay.
erk_relay -> erk_output Provides Input For
Active ERK phosphorylates nuclear and cytoplasmic substrates.
mapk_negative_regulation -> erk_mapk Negatively Regulates
DUSP/MKP phosphatases dephosphorylate ERK.
ERK/FGF signalling induces Sprouty expression, closing the Sprouty negative-feedback loop onto the Ras switch and the RAF tier.
PMID:31761616
Sprouty expression is induced by ERK activation as negative feedback.
SPRY expression was previously reported to be induced by ERK activation as a negative feedback
PMID:11238463
Mammalian and chicken Sprouty genes are upregulated by FGF signalling.
expression of mSprys and chicken Sprys is also upregulated by the FGF signaling pathway
SPRY2 sequesters GRB2 away from SOS and SPRED recruits the RasGAP NF1, both lowering Ras-GTP.
sprouty_spred_feedback -> erk_relay Negatively Regulates
SPRY4 binds RAF1 and blocks its activation.
The ERK transcriptional program induces the immediate-early phosphatases MKP-1/MKP-2 (DUSP1/DUSP4), closing the DUSP negative-feedback loop.
PMID:8995446
The dual specificity mitogen-activated protein kinase phosphatase-1 and -2 are induced by the p42/p44MAPK cascade.
MKP-1 and MKP-2 induction requires the p42/p44 MAPK cascade and temporally correlates with MAPK inactivation.
activation of the p42/p44MAPK cascade promotes the induction of MKP-1 and MKP-2, which may then attenuate p42/p44MAPK-dependent events
erk_mapk -> raf_map3k Negatively Regulates
Active ERK feedback-phosphorylates RAF (six S/TP sites on Raf-1, four on B-Raf), which blocks Ras binding and desensitizes the MAP3K tier until PP2A/Pin1 recycle it.
PMID:15664191
Regulation of Raf-1 by direct feedback phosphorylation.
ERK-dependent hyperphosphorylation of Raf-1 inhibits the Ras/Raf-1 interaction and desensitizes Raf-1.
Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.
PMID:19933846
Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signaling.
B-Raf is subject to the same ERK-dependent feedback phosphorylation, which inhibits binding to activated Ras.
We identify four S/TP sites of B-Raf phosphorylated by activated ERK and find that feedback phosphorylation of B-Raf inhibits binding to activated Ras
file:models/boolean/bbm-070-mapk-cancer-cell-fate/model.bnet
The published MAPK logical model (Grieco 2013, PMID:24250280) carries ERK as an inhibitor in the RAF update rule.
file:models/boolean/signor/SIGNOR-EGF.tsv
SIGNOR-EGF records ERK1/2 down-regulating BRAF by phosphorylation of Thr401 (direct; PMID:21135229).
erk_mapk -> ras_gef_step Negatively Regulates
Active ERK directly phosphorylates the C-terminal proline-rich region of SOS1 on multiple MAPK sites, weakening GRB2-SOS binding and uncoupling SOS from the receptor: a direct negative feedback onto the Ras switch.
PMID:8816480
Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2.
Five MAPK sites in the C-terminal domain of hSos1 regulate Grb2 binding; alanine substitution increases Grb2 affinity.
Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1
file:models/boolean/signor/SIGNOR-EGF.tsv
SIGNOR-EGF records ERK1/2 down-regulating SOS1 activity by phosphorylation of Ser1132/Ser1167/Ser1197 (direct; PMID:8816480).
erk_output -> ras_gef_step Negatively Regulates
The ERK substrate kinase RSK (part of the ERK effector output step) phosphorylates SOS1 on further C-terminal sites (Ser1134/Ser1161), creating 14-3-3 docking sites: a second, one-step-delayed negative feedback onto the Ras switch, and the route the published MAPK logical model uses (RSK -| SOS).
PMID:22827337
RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation.
RSK phosphorylates SOS1 on Ser1134/Ser1161, creating 14-3-3 sites; mutating them extends MAPK activation.
RSK phosphorylates the Ras activator SOS1 (Son of Sevenless homologue 1) in cultured cells on two C-terminal residues, Ser(1134) and Ser(1161)
PMID:9242373
EGF induced SOS phosphorylation in PC12 cells involves P90 RSK-2.
p90 RSK-2, downstream of MAP kinase, is a major SOS kinase after EGF stimulation and down-regulates Ras activation through SOS.
a major mitogen activated kinase for SOS is p90 Rsk-2, a downstream target of MAP kinase
file:models/boolean/bbm-070-mapk-cancer-cell-fate/model.bnet
The published MAPK logical model (Grieco 2013, PMID:24250280) carries RSK as an inhibitor in the SOS update rule.
Part 1: receptor-proximal adaptor recruitment
GRB2/SHC adaptor recruitment to receptor phosphotyrosineRegulatory Stepadaptor_recruitment

SH2-domain adaptors (GRB2 directly, or SHC then GRB2) recognize a phosphotyrosine motif on an activated receptor (or receptor-associated kinase) and use their SH3 domains to recruit the Ras GEF SOS to the membrane. This step couples the upstream receptor to the Ras switch.

Annotons

GRB2/SHC adaptor function
grb2_shc_adaptor
Participant: Family: GRB2/SHC adaptor proteins
Family:
GRB2/SHC adaptor proteins SH2/SH3 (GRB2) and PTB/SH2 (SHC) adaptors that link receptor phosphotyrosines to SOS.

Function

phosphotyrosine residue bindingGO:0001784 SH2/PTB recognition of the activated-receptor phosphotyrosine docking site.

Bridges the activated receptor to the Ras guanine nucleotide exchange factor.

Part 2: Ras nucleotide switch (conforms to gtpase_switch)
Ras GTPase nucleotide switch (SOS / Ras / RasGAP)Reactionras_nucleotide_switch

The Ras nucleotide switch: the GEF SOS loads GTP onto Ras (HRAS/KRAS/ NRAS), the GTP-bound GTPase activates RAF, and RasGAPs (e.g. NF1) accelerate GTP hydrolysis to switch Ras off. This bundle is an instance of the generic GTPase nucleotide switch.

Ras protein signal transductionGO:0007265

Connections

SOS loads GTP onto Ras, activating the switch.
rasgap_step -> ras_active Negatively Regulates
RasGAPs accelerate hydrolysis to switch Ras off.
Part 1: GEF tier (SOS)
SOS guanine nucleotide exchange on RasReactionras_gef_step

The recruited GEF SOS1/SOS2 catalyzes GDP-for-GTP exchange on Ras.

Annotons

SOS Ras GEF activity
sos_gef
Participant: Family: SOS Ras GEFs
Family:
SOS Ras GEFsPANTHER:PTHR23113 Son-of-sevenless guanine nucleotide exchange factors SOS1/SOS2.
Representative Members: SOS1UniProtKB:Q07889

Function

guanyl-nucleotide exchange factor activityGO:0005085
Targets: Ras GTPase

Loads GTP onto Ras, activating the switch.

Part 2: active GTPase tier (Ras)
Active GTP-bound RasReactionras_active

GTP-bound Ras (HRAS, KRAS, or NRAS) adopts the active conformation and recruits/activates RAF kinases; intrinsic and GAP-stimulated hydrolysis resets the switch.

Annotons

Part 3: GAP tier (RasGAP)
RasGAP acceleration of Ras GTP hydrolysisReactionrasgap_step

RasGAPs (e.g. NF1/neurofibromin, RASA1) stimulate Ras GTP hydrolysis to switch Ras off.

Annotons

RasGAP function
rasgap_role
Participant: Family: RasGAPs (e.g. NF1, RASA1)
Family:
RasGAPs (e.g. NF1, RASA1)PANTHER:PTHR10194 GTPase-activating proteins that switch Ras off.
Representative Members: NF1 (neurofibromin)UniProtKB:P21359 RASA1 (p120RasGAP)UniProtKB:P20936

Function

GTPase activator activityGO:0005096

Stimulates Ras GTP hydrolysis to switch Ras off.

Part 3: ERK kinase relay (conforms to mapk_relay)
ERK kinase relay (RAF -> MEK -> ERK)Reactionerk_relay

The three-tier kinase relay of the ERK cascade: GTP-Ras-activated RAF (MAP3K) phosphorylates MEK1/2 (MAP2K), which dually phosphorylates ERK1/2 (MAPK) on its TEY activation-loop motif. This bundle is an instance of the generic three-tier MAP kinase relay.

Connections

raf_map3k -> mek_map2k Causes
RAF phosphorylates and activates MEK1/2.
mek_map2k -> erk_mapk Causes
MEK dually phosphorylates ERK1/2.
Part 1: MAP3K tier (RAF)
RAF MAP kinase kinase kinase activationReactionraf_map3k

Active Ras recruits RAF kinases (RAF1/CRAF, BRAF, ARAF) to the membrane, where they dimerize and become active MAP3Ks that phosphorylate MEK.

Annotons

RAF MAP3K activity
raf_kinase
Participant: Family: RAF kinases
Family:
RAF kinasesPANTHER:PTHR44329 RAF1/CRAF, BRAF, ARAF serine/threonine MAP3Ks.
Representative Members: BRAFUniProtKB:P15056 RAF1 (CRAF)UniProtKB:P04049

Function

MAP kinase kinase kinase activityGO:0004709
Targets: MEK1/MEK2

Top kinase tier; phosphorylates and activates MEK.

Part 2: MAP2K tier (MEK)
MEK1/MEK2 MAP kinase kinase activationReactionmek_map2k

RAF phosphorylates the dual-specificity MAP2Ks MEK1 (MAP2K1) and MEK2 (MAP2K2), which in turn phosphorylate ERK on both threonine and tyrosine of its activation-loop TEY motif.

Annotons

MEK MAP2K activity
mek_kinase
Participant: Family: MEK1/MEK2 (MAP2K1/MAP2K2)
Family:
MEK1/MEK2 (MAP2K1/MAP2K2)PANTHER:PTHR48013 Dual-specificity MAP kinase kinases dedicated to the ERK tier.
Representative Members: MEK1 (MAP2K1)UniProtKB:Q02750 MEK2 (MAP2K2)UniProtKB:P36507

Function

MAP kinase kinase activityGO:0004708
Targets: ERK1/ERK2 TEY motif

Middle kinase tier; dual-specificity activation of ERK.

Part 3: MAPK tier (ERK)
ERK1/ERK2 MAP kinase activationReactionerk_mapk

Dually phosphorylated ERK1 (MAPK3) and ERK2 (MAPK1) become active proline-directed serine/threonine kinases, dimerize, and act on cytoplasmic and (after nuclear translocation) nuclear substrates.

Annotons

ERK1/ERK2 MAP kinase activity
erk_kinase
Participant: Family: ERK1/ERK2 (MAPK3/MAPK1)
Family:
ERK1/ERK2 (MAPK3/MAPK1)PANTHER:PTHR24055 The terminal effector kinases of the classical MAPK cascade.
Representative Members: ERK2 (MAPK1)UniProtKB:P28482 ERK1 (MAPK3)UniProtKB:P27361

Function

MAP kinase activityGO:0004707

Locations

nucleusGO:0005634

Effector kinase that transduces the cascade output to substrates.

Part 4: ERK transcriptional and effector output
ERK effector and transcriptional outputRegulatory Steperk_output

Active ERK phosphorylates nuclear transcription factors and kinases (ELK1 and other Ets factors, RSK, MSK) and numerous cytoplasmic substrates, driving immediate-early gene transcription, cell-cycle entry, proliferation, and differentiation.

Annotons

ERK substrate phosphorylation and transcriptional activation
erk_substrate_output
Participant: Any With Function: MAP kinase activity
Required Function:
MAP kinase activityGO:0004707

Processes

positive regulation of transcription by RNA polymerase IIGO:0045944

Converts ERK activity into a proliferation/differentiation gene program.

RSK (p90 ribosomal S6 kinase) effector activity
rsk_kinase
Participant: Family: RSK (p90 ribosomal S6 kinases, RPS6KA1-3/6)
Family:
RSK (p90 ribosomal S6 kinases, RPS6KA1-3/6) ERK-activated AGC kinases that carry part of the ERK output (CREB/SRF-family and translational substrates) and feed back onto SOS1.
Representative Members: RPS6KA1 (RSK1)UniProtKB:Q15418 RPS6KA3 (RSK2)UniProtKB:P51812

Function

protein serine/threonine kinase activityGO:0004674
Targets: SOS1 C-terminal serines (Ser1134/Ser1161)UniProtKB:Q07889

The ERK substrate kinase whose phosphorylation of SOS1 is the actor behind the erk_output -| ras_gef_step feedback connection.

Part 5: DUSP/MKP negative feedback on ERK
DUSP/MKP dephosphorylation of ERKReactionmapk_negative_regulation

DUSP/MKP dual-specificity phosphatases dephosphorylate the ERK activation loop to terminate signaling. MKP-1/MKP-2 (DUSP1/DUSP4) are immediate-early products of the ERK transcriptional program itself, so this step is both a basal input and an ERK-induced negative feedback (closed by the erk_output -> mapk_negative_regulation connection). RasGAP-mediated switch-off of Ras is captured inside the Ras nucleotide switch bundle.

Annotons

DUSP/MKP phosphatase function
dusp_role
Participant: Family: DUSP/MKP dual-specificity phosphatases
Family:
DUSP/MKP dual-specificity phosphatasesPANTHER:PTHR10159 ERK-inactivating dual-specificity (Thr/Tyr) MAP kinase phosphatases. The cytoplasmic ERK-selective member DUSP6 (MKP-3) is the representative; it is induced by FGF/ERK signalling and allosterically activated by binding ERK.
Representative Members: DUSP6UniProtKB:Q16828

Function

MAP kinase tyrosine/serine/threonine phosphatase activityGO:0017017

Processes

negative regulation of ERK1 and ERK2 cascadeGO:0070373

Locations

cytosolGO:0005829

Dephosphorylates the ERK activation loop to terminate signaling.

PMID:8670865
Like CL100/ MKP-1, Pyst1 dephosphorylates and inactivates MAP kinase in vitro and in vivo.
file:genes/human/DUSP6/DUSP6-ai-review.yaml
DUSP6 (Pyst1/MKP-3) review core functions MAP kinase tyrosine/serine/threonine phosphatase activity (GO:0017017) and MAP kinase binding in negative regulation of the ERK1/2 cascade (GO:0070373).
Part 6: Sprouty/SPRED negative feedback on Ras-RAF (optional)
Sprouty/SPRED feedback inhibition of Ras-RAF activationRegulatory Stepsprouty_spred_feedback

Sprouty (SPRY1, SPRY2, SPRY4) and SPRED (SPRED1, SPRED2) proteins damp signalling into the ERK relay, mostly at the level of SOS-Ras-RAF. Sprouty expression is induced by ERK signalling, closing a negative-feedback loop. The paralogs reach the same outcome by different molecular routes, so each mechanism is its own variant with its own molecular function rather than one shared activity.

Variant set: Sprouty/SPRED paralogs and their mechanisms by paralog (One Or More)

Union over the Sprouty (PTHR12365) and SPRED (PTHR11202) families. Variants are split by mechanism. SPRY2 also binds CBL (with CIN85) and blocks EGFR ubiquitination, which sustains EGFR signalling; that opposite-sign activity is recorded in the SPRY2 review and is not part of this feedback step.

Sprouty GRB2 sequestration (SPRY2)Regulatory Stepspry_grb2_variant

SPRY2 binds the GRB2 SH3 domain through a C-terminal PXXPXR motif that no other Sprouty paralog has, keeping GRB2-SOS from docking on FRS2 or SHP2. Whether this binding is required for ERK inhibition is contested (Lao 2007 versus Martinez 2007). SPRY1 lacks the motif; a reported phospho-Tyr53-dependent SPRY1-GRB2 interaction is disputed and is not modelled here.

Annotons

Sprouty GRB2 sequestering activity
spry_grb2_sequestration
Participant: Family: SPRY2 orthologs
Family:
SPRY2 orthologsPANTHER:PTHR12365:SF8
Representative Members: SPRY2UniProtKB:O43597

Function

protein sequestering activityGO:0140311

Processes

negative regulation of Ras protein signal transductionGO:0046580 negative regulation of ERK1 and ERK2 cascadeGO:0070373

Holds GRB2 away from FRS2 and SHP2 so SOS is not recruited.

PMID:12402043
Next, they bind to the adaptor protein Grb2 and inhibit the recruitment of the Grb2-Sos complex either to the fibroblast growth factor receptor (FGFR) docking adaptor protein FRS2 or to Shp2.
PMID:16893902
Spry2 is considerably more inhibitory than Spry1 or Spry4, and this correlates with the binding to Grb2 via a C-terminal proline-rich sequence that is found exclusively on Spry2.
file:genes/human/SPRY2/SPRY2-ai-review.yaml
SPRY2 review core functions GRB2 sequestering activity (GO:0140311) and RAF antagonism (GO:0004860).
Sprouty kinase inhibition (SPRY1, SPRY2, SPRY4)Regulatory Stepspry_raf_variant

SPRY4 binds RAF1 through its C-terminal cysteine-rich Sprouty domain and blocks Ras-independent RAF1 activation (e.g. by VEGF); it does not block EGF-induced, Ras-dependent RAF1 activation. SPRY4 lacks the SPRY2-specific C-terminal PxxPxR GRB2 SH3-binding motif. The same cysteine-rich domain directly inhibits the kinase TESK1. SPRY1 and SPRY2 carry the same inherited protein kinase inhibitor activity (PAINT family node), with SPRY4 as the experimentally characterized member.

Annotons

Sprouty RAF kinase inhibition
spry_raf_inhibition
Participant: Family: Sprouty paralogs
Family:
Sprouty paralogsPANTHER:PTHR12365
Representative Members: SPRY1UniProtKB:O43609 SPRY2UniProtKB:O43597 SPRY4UniProtKB:Q9C004

Function

protein kinase inhibitor activityGO:0004860

Processes

negative regulation of Ras protein signal transductionGO:0046580 negative regulation of ERK1 and ERK2 cascadeGO:0070373

Binds RAF1 and prevents its activation.

PMID:12717443
Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1.
file:genes/human/SPRY1/SPRY1-ai-review.yaml
SPRY1 review core function protein kinase inhibitor activity (GO:0004860, inherited family IBA); a GRB2-sequestering activity was not supported after an OpenScientist motif analysis.
file:genes/human/SPRY4/SPRY4-ai-review.yaml
SPRY4 review core function protein kinase inhibitor activity (GO:0004860) in negative regulation of ERK1/2, FGFR and Ras signalling.
SPRED neurofibromin recruitment (SPRED1, SPRED2)Regulatory Stepspred_nf1_variant

SPRED proteins bind the Ras GAP neurofibromin (NF1) through their EVH1 domain and use their membrane-anchored SPR domain to bring it to the plasma membrane, where NF1 converts Ras-GTP to Ras-GDP. SPRED has no catalytic activity; the GAP step itself sits in the Ras nucleotide switch. Sprouty proteins lack the EVH1 domain and do not bind neurofibromin.

Annotons

SPRED neurofibromin membrane recruitment
spred_nf1_recruitment
Participant: Family: SPRED paralogs
Family:
SPRED paralogsPANTHER:PTHR11202
Representative Members: SPRED1UniProtKB:Q7Z699 SPRED2UniProtKB:Q7Z698

Function

protein-membrane adaptor activityGO:0043495

Processes

negative regulation of Ras protein signal transductionGO:0046580 negative regulation of ERK1 and ERK2 cascadeGO:0070373

Recruits neurofibromin to the plasma membrane to switch Ras off.

PMID:22751498
However, Sprouty proteins, which lack the N-terminal EVH1 domain, did not coprecipitate neurofibromin.
file:genes/human/SPRED1/SPRED1-ai-review.yaml
SPRED1 review core function protein-membrane adaptor activity (GO:0043495, NEW) recruiting NF1, supported by the SPRED1 EVH1-NF1-KRAS structure; Legius syndrome EVH1 variants lose NF1 binding.
file:genes/human/SPRED2/SPRED2-ai-review.yaml
SPRED2 review core function protein-membrane adaptor activity (GO:0043495) recruiting NF1 to the membrane.