MAPK Cascades: Module and Gene Review Coverage

Overview

The generic three-tier MAP kinase relay (MAP3K -> MAP2K -> MAPK) is captured as
the abstract module mapk_relay. Six concrete cascade
modules conform to it:

Module	Cascade	Relay (MAP3K -> MAP2K -> MAPK)
erk_cascade	Ras-RAF-MEK-ERK1/2	RAF -> MEK1/2 -> ERK1/2
p38_cascade	p38 (stress)	ASK1/TAK1/MLK -> MKK3/6 -> p38
jnk_cascade	JNK (stress)	MEKK1/ASK1/MLK -> MKK4/7 -> JNK1-3
erk5_cascade	ERK5	MEKK2/3 -> MEK5 -> ERK5
scer_hog1_cascade	S. cerevisiae HOG (Sln1 branch)	Ssk2/Ssk22 -> Pbs2 -> Hog1
scer_mating_fus3_cascade	S. cerevisiae pheromone	Ste11 -> Ste7 -> Fus3/Kss1

This project tracks (1) PANTHER grounding of the module family descriptors and
(2) gene review coverage of the proteins that fill each tier, in human and in
representative model organisms.

PANTHER grounding of family descriptors

Family descriptors now carry family-level PANTHER ids, each checked against the
PANTHER membership index (built into .cache/panther/ by
just ensure-panther-members) or the family entries file:

Tier	PANTHER family	Used by
MAPK	PTHR24055 (MITOGEN-ACTIVATED PROTEIN KINASE)	ERK1/2, p38, JNK, ERK5, Fus3/Kss1
MAP2K	PTHR48013 (...KINASE KINASE 5-RELATED)	MEK1/2, MKK3/6, MKK4/7, MEK5 (also contains Pbs2, Ste7, worm SEK-1)
MAP3K, MEKK group	PTHR24361 (MITOGEN-ACTIVATED KINASE KINASE KINASE)	MEKK2/MEKK3
MAP3K, RAF	PTHR44329 (TNNI3K-RELATED; contains BRAF, RAF1, ARAF)	RAF kinases
MAP3K, yeast osmostress	PTHR48016 (SSK2-RELATED-RELATED)	Ssk2/Ssk22
Ras switch	PTHR24070, PTHR23113, PTHR10194	Ras, SOS, RasGAP

Deliberately left without an id: the stress MAP3K descriptors of the p38 and JNK
modules (ASK1, TAK1, MLK and MEKK1 sit in unrelated PANTHER families), the
GRB2/SHC adaptor descriptor, and the DUSP/MKP phosphatase descriptors.

PANTHER subfamilies were not used. The validator suggests them where all listed
members share one, but they are not clean paralog groups for these kinases:
PTHR48013:SF9 is named for MEK5 but also contains yeast Ste7 and plant MKKs.

PAINT ancestral nodes

Family descriptors also carry PAINT IBD nodes from the local
interpro/panther/*/*-paint.tsv slices, each seeded by the descriptor's own
representative members:

Descriptor	PAINT node	Propagated terms
Ras GTPases	PTN000631348, PTN008604616	GTPase activity; Ras protein signal transduction
RasGAPs	PTN008939999	GTPase activator activity
SOS	PTN000560991	guanyl-nucleotide exchange factor activity
RAF	PTN001147804	MAP kinase kinase kinase activity; MAPK cascade
ASK-subgroup MAP3Ks (p38)	PTN000684847	MAP kinase kinase kinase activity
MEK1/2, MKK3/6, MKK4/7	PTN000684494	MAP kinase kinase activity; MAPK cascade
JNK	PTN001171982, PTN000622075	JUN kinase activity; JNK cascade; plus the MAPK-wide node
ERK1/2, p38, ERK5	PTN000622075	MAPK-wide node (Ser/Thr kinase, intracellular signal transduction, nucleus, cytoplasm)

Not added: MEK5 and MEKK2/3 (not seeds of
a matching node), and Fus3/Kss1 and Hog1 (the yeast seeds are SGD ids that
cannot be mapped to genes offline). The p38 module previously described
PTN000684847 as a p38 MAPK node; it is an ASK-subgroup MAP3K node (seeds ASK1,
MAP3K6, MAP3K15) and the evidence text was corrected.

The membership index was refreshed on 2026-09-24. The old index had MEK2 in
PTHR47448; the current PANTHER classification puts MEK1 and MEK2 in PTHR48013,
consistent with the PAINT tree (both are seeds of PTN000684494), so the MEK
descriptor now uses PTHR48013. One PAINT/HMM mismatch remains: MEKK1/2/3 are
seeds of PTN004700021 in the PTHR48013 PAINT slice, while the membership index
puts them in PTHR24361.

The yeast HOG and mating modules name their proteins as single gene products,
not family members, so Pbs2, Hog1, Ste11, Ste7 and the Sln1/Ypd1/Ssk1
phosphorelay are not in the membership index.

Gene review coverage

Status as of 2026-09-23. "Done" means the review exists with all existing
annotations actioned and core_functions filled.

ERK1/2 (erk_cascade)

Tier	Done	To do
Adaptor	human GRB2, SHC1 (2026-09-27); mouse Grb2	-
Ras GEF	human SOS1, SOS2 (2026-09-27)	-
Ras	human HRAS, KRAS, NRAS; mouse Kras, Hras	finish human NRAS (status INITIALIZED); deep research for NRAS
RasGAP	human NF1, RASA1	-
RAF (MAP3K)	human BRAF; RAF1, ARAF (2026-09-27)	-
MEK (MAP2K)	human MAP2K1 (2026-09-27), MAP2K2; horse MAP2K2	-
ERK (MAPK)	human MAPK1, MAPK3 (2026-09-27); mouse Mapk1, Mapk3; rat Mapk1	-
Invertebrates	-	fly rl, Dsor1, phl; worm mpk-1, mek-2, lin-45, let-60, sem-5

p38 (p38_cascade)

Tier	Done	To do
MAP3K	human MAP3K5, MAP3K20; worm nsy-1	human MAP3K7
MAP2K	human MAP2K3, MAP2K6 (2026-09-24); worm sek-1; S. pombe wis1 (DRAFT)	-
MAPK	human MAPK14 (2026-09-24); worm pmk-1; S. pombe sty1 (DRAFT)	human MAPK11, MAPK12, MAPK13

JNK (jnk_cascade)

Done (2026-09-25, all COMPLETE): human MAP3K1, MAP2K4, MAP2K7, MAPK8. MAP2K4
and MAP2K7 use GO:0008545 JUN kinase kinase activity as core MF; MAP3K1 gains
tubulin binding (TOG domain). To do: human MAPK9, MAPK10; fly bsk, hep; worm
jnk-1, kgb-1. Follow-up: PMID:19593445 (a BAD/prostate cancer paper) is cited
for IEP "cellular response to mechanical stimulus" on MAP3K1, MAP2K4, MAPK8
and other genes and looks like a batch mis-citation (rows left UNDECIDED).

ERK5 (erk5_cascade)

Done (2026-09-25, all COMPLETE): human MAP3K2, MAP3K3, MAP2K5, MAPK7. MAPK7
gains transcription coactivator activity (kinase-independent MEF2
transactivation); MAP3K3 keeps a second core role in canonical NF-kB
activation.

S. cerevisiae HOG (scer_hog1_cascade)

Done (2026-09-24, all COMPLETE): SLN1, YPD1, SSK1, SSK2, SSK22, PBS2, HOG1.
Follow-ups raised in the reviews: three UniProt-assigned NatB rows on PBS2
(PMID:12783868) look like a NAT3 mis-attribution and are UNDECIDED; the
GO:0009927 definition fits Ypd1's relay role better than hybrid kinases such
as Sln1.

S. cerevisiae mating (scer_mating_fus3_cascade)

Done (2026-09-24, all COMPLETE): STE11, STE7, FUS3, KSS1, STE5. STE5 gains
protein serine/threonine kinase activator activity (Ste7->Fus3 co-catalysis);
KSS1 gains negative regulation of invasive growth (kinase-independent Ste12
repression); STE11 raises moving SGD annotations to GO:0062031 filamentous
growth MAPK cascade. Note that
genes/SCHPO/ste11 is an unrelated HMG-box transcription factor; the
S. pombe relative of budding-yeast STE11 is byr2.

Phosphatase feedback (DUSP/MKP)

No DUSP reviews in any species. To do: human DUSP1, DUSP4, DUSP6, DUSP10, DUSP16.

Suggested order

1. ~~Yeast HOG and mating cascades~~ (done 2026-09-24).
2. ~~The human p38 tier proteins (MAP2K3, MAP2K6, MAPK14)~~ (done 2026-09-24).
3. ~~Human JNK and ERK5 relays~~ (done 2026-09-25).
4. ~~Remaining ERK gaps (MAP2K1, MAPK3, RAF1, ARAF, GRB2, SHC1, SOS1, SOS2)~~ (done 2026-09-27); then DUSPs.
5. Invertebrate orthologs.

Gene reviews need just fetch-gene, which needs network access to UniProt,
QuickGO and PubMed.