MAPK8 (JNK1) curation notes

UniProt P45983; HGNC MAPK8; synonyms JNK1, SAPK1c, PRKM8. CMGC Ser/Thr kinase, MAP kinase
subfamily, JNK branch (InterPro IPR008351 MAPK_JNK; PANTHER PTHR24055).

Identity and activation

• Proline-directed Ser/Thr MAP kinase; activation-loop TPY motif (Thr183/Tyr185).
  [file:human/MAPK8/MAPK8-uniprot.txt "Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4"]
• MKK4 prefers Tyr185, MKK7 prefers Thr183; the two act synergistically.
  PMID:11062067
• MKK7 docks on JNK1 through three N-terminal D-sites; D-site peptides compete with substrates.
  PMID:16533805
• Pin1 isomerises the phospho-Thr-Pro in the activation loop, promoting activation and substrate association.
  PMID:21660049
• Inactivated by dual-specificity phosphatases (MKP-7/DUSP16, DUSP8, MKP-1).
  PMID:11489891
• Scaffolds: JIP1/MAPK8IP1, JIP2/MAPK8IP2, JIP3, JIP4. JIP1 also retains JNK1 in the cytoplasm and
  inhibits it (structural basis PMID:15141161).
  PMID:15141161

Molecular function (core)

• MAP kinase activity (GO:0004707), JUN kinase activity (GO:0004705): c-Jun Ser63/73, ATF2, Elk-1.
  PMID:8654373
• JDP2 and ATF2 phosphorylated by human JNK1 co-expressed in E. coli (direct activity).
  PMID:18307971
• Many other direct substrates (all with in vitro kinase evidence):
• HSF1 (inhibitory) PMID:10747973
• BAD Thr201 (pro-survival) PMID:14967141; EPO-driven in erythroid cells PMID:21095239
• SIRT1 Ser27/Ser47/Thr530 PMID:20027304
• SIRT6 Ser10 PMID:27568560
• YAP PMID:21364637
• Cdt1 Thr29 PMID:21856198
• NFAT3 Ser213/217 PMID:17875713
• 4E-T/EIF4ENIF1 (P-body assembly) PMID:22966201
• BMAL1/CLOCK PMID:22441692
• NLRP3 Ser194 (inflammasome priming) PMID:28943315
• ALKBH5 (ERK/JNK) PMID:34048572
• BIM, BMF (release from dynein/myosin V motor complexes) [Reactome:R-HSA-139918, R-HSA-139908]
• BCL2 (autophagy) PMID:26546165
• Elk-1 (via Rev7) PMID:17296730; HSF4b PMID:16581800; CapZIP PMID:15850461

Processes

• Core: JNK cascade (GO:0007254) / stress-activated MAPK cascade (GO:0051403); terminal kinase tier.
• Downstream/pleiotropic (non-core): apoptosis (both pro- and anti-apoptotic depending on context:
  BIM/BMF release vs BAD inactivation), autophagy (BCL2), NLRP3 inflammasome priming, circadian
  photic response, DNA repair (SIRT6), energy homeostasis/insulin resistance (mouse), neuronal
  development (basal dendrites; mouse TAOK2 paper PMID:22683681), responses to UV, ROS, LPS,
  amino acid (glutamine) deprivation.
• Inhibitor-only (SP600125) evidence cannot distinguish JNK1/2/3: CD38 induction/cyclase activity
  (PMID:22027397), DR5 expression (PMID:22065586; JNK siRNA not isoform specific).

Localization

• Cytoplasm and nucleus; active JNK translocates to nucleoplasm to phosphorylate TFs.
  [Reactome:R-HSA-450348 "c-Jun NH2 terminal kinase (JNK) plays a role in conveying signals from the cytosol to the nucleus"]
• HA-JNK1 uniform cytoplasm + nucleus PMID:22966201
• Neuronal: axons/synapses (rodent, ISS).

Annotation issues noted

• GO:1903749 (TAS, Reactome BIM/BMF) is obsolete in current GO (QuickGO: "represents a phenotype and was
  added in error"); replace with positive regulation of intrinsic apoptotic signaling pathway (GO:2001244).
• GO:0120283 IPI PMID:11865055 WITH/FROM UniProtKB:P27448 (MARK3, "C-TAK1"), but the paper studies
  TAK1 = MAP3K7 ("XIAP, NAIP, and JNK1 bind to TAK1"). The term remains correct (TAK1 is a Ser/Thr
  kinase) but the partner identifier looks mis-mapped.
• GO:0071260 IEP PMID:19593445: the cached full text (BAD in prostate cancer) never mentions JNK or a
  mechanical stimulus; could not verify -> UNDECIDED.
• GO:0005515 rows: replaced with partner-class MFs consistent with MAPK14/MAPK1 reviews
  (MAPKK binding, scaffold protein binding, protein phosphatase binding, protein kinase binding,
  DNA-binding transcription factor binding); non-informative partners (CBL, PIK3R1, CLDN6, RPTOR,
  EIF4ENIF1, Pdcd4, MECOM, APBB1) removed.
• GO-CAMs: 635b1e3e00002004 (NLRP3 inflammasome, MAPK8 kinase -> positive regulation of NLRP3
  inflammasome assembly), 622aace900000522 (SIRT6/oxidative stress), 6494e2e900002525 (energy homeostasis).

Isoform/paralog caveat

Most "JNK" literature uses pan-JNK reagents (SP600125, phospho-JNK antibodies). JNK1 and JNK2 are
redundant for many functions (shared PAINT node PTN001171982), so process annotations based on
inhibitor data are weak for MAPK8 specifically.

Review session log (2026-09-25)

Audited the notes above against cached sources (quotes used in the review were checked by the
reference validator). Final decisions in MAPK8-ai-review.yaml:

• Core: GO:0004707 MAP kinase activity / GO:0004705 JUN kinase activity in GO:0007254 JNK cascade
  (IBA PTN001171982 accepted; consistent with modules/jnk_cascade.yaml). GO:0106310 and GO:0004674
  experimental rows accepted (as in MAPK14).
• GO:0005515 rows: MKK4/MKK7 -> GO:0031434; JIP1/JIP2/JIP-1b -> GO:0097110; DUSP8 -> GO:0019903;
  JNK2 -> GO:0019901 (MAPK14 convention); c-Jun and HSF1 -> GO:0140297. Removed: MECOM, Pdcd4, CBL,
  PIK3R1 (x2), APBB1, H2AX, EIF4ENIF1, RPTOR, CLDN6.
• GO:0120283 (TAK1 row): full text confirms TAK1 = MAP3K7 ("TAK1 is an upstream MAP3 kinase that
  activates JNK1 and p38"); WITH/FROM P27448 (MARK3/C-TAK1) looks mis-mapped. MODIFY -> GO:0031435.
• GO:1903749 (obsolete per QuickGO) x2 -> GO:2001244 positive regulation of intrinsic apoptotic
  signaling pathway.
• GO:0035033 histone deacetylase regulator activity: MARK_AS_OVER_ANNOTATED (kinase acting on SIRT1).
• GO:0071260 IEP PMID:19593445 and GO:0009612 IBA (PTN008602925, only descendant = MAPK8 itself):
  UNDECIDED, same stance as MAP2K4/MAP3K1.
• Inhibitor/pan-JNK process rows (CD38 cyclase, protein metabolic process, DR5 gene expression) and
  Reactome cell killing: MARK_AS_OVER_ANNOTATED.