MAPK14 (p38 alpha, Q16539) curation notes

Identity and core biochemistry

MAPK14 encodes p38 alpha (SAPK2a, CSBP), a CMGC-group, proline-directed Ser/Thr MAP kinase.
First identified as the target of pyridinyl-imidazole cytokine-suppressive anti-inflammatory
drugs PMID:7997261.
Activation by dual phosphorylation of the TGY motif PMID:7535770, by MKK3/MKK6
(MAP2K3/MAP2K6) and, atypically, TAB1-driven autophosphorylation [file:human/MAPK14/MAPK14-uniprot.txt
"Activation occurs through dual phosphorylation of Thr-180 and Tyr-182 by either of two dual
specificity kinases, MAP2K3/MKK3 or MAP2K6/MKK6"].
Located in both cytoplasm and nucleus PMID:7535770.
Rhea reactions for serine and threonine phosphorylation are curated (EC 2.7.11.24) from
PMID:11010976 and PMID:35857590.

Kinase substrates: MK2/MK3 (MAPKAPK2/3), MSK1/2 (RPS6KA5/4), MNK1/2, MK5/PRAK. The p38alpha-MK2
heterodimer crystal structure shows the MK2 C-terminal regulatory region in the p38 docking groove
PMID:17255097.
MSK2/RSK-B is a p38alpha substrate PMID:9792677.
Transcription factors: MEF2A/C via D-domain docking PMID:10330143; USF1 Thr153 PMID:11532965; ATF2, CREB (via MSK).
RNA regulators: TIAR during DNA-damage checkpoint maintenance PMID:20932473.
Innate immunity: NLRP1 disordered linker in the ZAKalpha ribotoxic stress response PMID:35857590.
Rb Ser567 PMID:20871633.

DUSP1, DUSP10/MKP-5, DUSP16, DUSP9/MKP-4, PTPRR/PTP-SL, PPM1D/WIP1, PPM1A. MKP-5 prefers p38
PMID:10391943. DUSP9 KIM-dependent binding PMID:21908610.
PTP-SL KIM binding PMID:10601328. LZAP/CDK5RAP3 recruits WIP1 PMID:21283629.

85 IPI rows. Partners were resolved from WITH/FROM via UniProt REST.
Kinases (MAPKAPK2, MAPKAPK3, RPS6KA4, RPS6KA5, MKNK1, MKNK2, MAPK3, CSNK1D) -> MODIFY to
GO:0019901 protein kinase binding (same choice as MAPK1 review).
MAP2K3, MAP2K6 -> MODIFY to GO:0031434 mitogen-activated protein kinase kinase binding.
DUSP1, DUSP7, DUSP9, DUSP16, PTPRR, PPM1A -> MODIFY to GO:0019903 protein phosphatase binding.
Non-enzyme partners (ZFP36L1, SUPT20H/p38IP, ZNHIT1/p18Hamlet, RB1, EEF1A1, TSC1, MIDEAS, FBXW7,
CDK5RAP3/LZAP) -> REMOVE (uninformative; interaction not disputed). Substrate relationships
(Rb, p18Hamlet) are better captured as has_input on the kinase activity.

Core: p38MAPK cascade (GO:0038066), stress-activated MAPK cascade (GO:0051403), MAPK cascade,
intracellular signal transduction.
Non-core (well supported, downstream): myogenic differentiation (MEF2; mouse ISS), senescence
and DNA-damage signalling PMID:20160708,
erythroid differentiation PMID:23483889, UV-B response, LPS
response, IL-12 and inflammatory cytokine production.
Over-annotation: single-context inhibitor (SB203580) outcomes such as positive regulation of
cyclase activity (CD38 expression in astrocytes, PMID:22027397), cellular response to virus
(dengue/Gal-9, PMID:25754930), response to lipoteichoic acid (PMID:26649771), generic positive
regulation of gene expression; Reactome neutrophil-degranulation compartments (extracellular
region, secretory granule lumen, ficolin-1-rich granule lumen) for a cytosolic kinase.
MAP kinase kinase activity (GO:0004708) TAS from PMID:10706854 is wrong: the eosinophil
study measures p38 activation and uses inhibitors; p38 is a MAPK, not a MAPKK -> REMOVE.
NOT positive regulation of blood vessel endothelial cell migration (PMID:18440775) is supported
by the abstract: p38alpha siRNA "had no significant effect on the chemotactic response to VEGF".
GO:0048273 (MAPK p38 binding) on MAPK14 itself with RSKB/MSK2 as partner describes the
partner's function; the MAPK14-side function is protein kinase binding -> MODIFY.

Mxi2 (Q16539-3) binds ERK1/2 and promotes their nuclear import PMID:17255949; Exip and Mxi2 have
divergent C-termini and reduced substrate affinity PMID:10838079. No GOA rows are isoform-tagged.
Many functional studies use SB203580/SB202190, which inhibit p38alpha and p38beta; process
claims from these are not strictly MAPK14-specific
[file:human/MAPK14/MAPK14-deep-research-falcon.md].