# MAP3K20 (Q9NYL2) research notes

## Summary
MAP3K20 (ZAK; also MLK7/MRK) is a stress-activated mitogen-activated protein kinase kinase kinase (MAP3K) of the MLK family. As a serine/threonine protein kinase it phosphorylates the MAP2Ks MKK4/MKK7 (activating JNK) and MKK3/MKK6 (activating p38), driving stress-activated MAPK (JNK and p38) signaling that can promote programmed cell death. The principal isoform ZAKalpha is the proximal sensor of the ribotoxic stress response and directly binds the ribosome by inserting its flexible C-terminus into the intersubunit space (contacting helix 14 of 18S rRNA), acting as a sentinel for colliding ribosomes. Ribosome collisions trigger MAP3K20 autophosphorylation and activation; depending on collision severity it either activates the JNK/p38 cascade to promote cell death or activates EIF2AK4/GCN2 to engage the integrated stress response. ZAKalpha also drives the UV-B-induced NLRP1 inflammasome and pyroptosis by phosphorylating NLRP1. A shorter isoform, ZAKbeta, lacks the ribosome-binding C-terminus and does not sense collisions. MAP3K20 localizes mainly to the cytoplasm/cytosol (with reported nuclear pools and histone H3 Ser-28 kinase activity). It has additional reported roles in DNA-damage checkpoint signaling and cardiac stress responses. Biallelic variants cause split-foot malformation with mesoaxial polydactyly (SFMMP) and centronuclear myopathy 6 (CNM6).

## Core functions (from review)
- **GO:0004709 MAP kinase kinase kinase activity** — Stress-activated serine/threonine MAP kinase kinase kinase that phosphorylates MAP2Ks (MKK4/MKK7 and MKK3/MKK6) to activate the JNK and p38 (stress-activated) MAPK cascades, driving stress responses that can promote programmed cell death.
- **GO:0043022 ribosome binding** — Proximal sensor of ribosome collisions in the ribotoxic stress response; isoform ZAKalpha directly binds the ribosome (inserting its C-terminus into the intersubunit space and contacting helix 14 of 18S rRNA), autophosphorylates upon collisions, and routes the signal to the JNK/p38 cell-death cascade or to GCN2-mediated integrated stress response.
- **GO:0004674 protein serine/threonine kinase activity** — Stress-activated MAPK signaling that triggers programmed cell death and, in response to UV-B/ribotoxic stress, the NLRP1 inflammasome and pyroptosis through direct NLRP1 phosphorylation.

## Provenance
Research and verbatim supporting quotes are recorded inline in `MAP3K20-ai-review.yaml` (per-annotation `supported_by` and `references` findings). This notes file summarizes the completed review; see the YAML for evidence citations.