MAP3K20
Domain
Isoform ZAKalpha
Recognizes stalled ribosomes via two separate and partially redundant sensor domains: the C-terminal domain (CTD) that binds the 18S ribosomal RNA (18S rRNA) and the sensing domain (S).
Function
Stress-activated component of a protein kinase signal transduction cascade that promotes programmed cell death in response to various stress, such as ribosomal stress, osmotic shock and ionizing radiation (PubMed:10924358, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15350844, PubMed:15737997, PubMed:18331592, PubMed:20559024, PubMed:26999302, PubMed:32289254, PubMed:32610081, PubMed:35857590). Acts by catalyzing phosphorylation of MAP kinase kinases, leading to activation of the JNK (MAPK8/JNK1, MAPK9/JNK2 and/or MAPK10/JNK3) and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways (PubMed:11042189, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15172994, PubMed:15737997, PubMed:32289254, PubMed:32610081, PubMed:35857590). Activates JNK through phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7, and MAP kinase p38 gamma (MAPK12) via phosphorylation of MAP2K3/MKK3 and MAP2K6/MKK6 (PubMed:11836244, PubMed:12220515). Involved in stress associated with adrenergic stimulation: contributes to cardiac decompensation during periods of acute cardiac stress (PubMed:15350844, PubMed:21224381, PubMed:27859413). May be involved in regulation of S and G2 cell cycle checkpoint by mediating phosphorylation of CHEK2 (PubMed:15342622).
Isoform ZAKalpha
Key component of the stress-activated protein kinase signaling cascade in response to ribotoxic stress or UV-B irradiation (PubMed:32289254, PubMed:32610081, PubMed:35857590). Acts as the proximal sensor of ribosome collisions during the ribotoxic stress response (RSR): directly binds to the ribosome by inserting its flexible C-terminus into the ribosomal intersubunit space, thereby acting as a sentinel for colliding ribosomes (PubMed:32289254, PubMed:32610081). Upon ribosome collisions, activates either the stress-activated protein kinase signal transduction cascade or the integrated stress response (ISR), leading to programmed cell death or cell survival, respectively (PubMed:32610081). Dangerous levels of ribosome collisions trigger the autophosphorylation and activation of MAP3K20, which dissociates from colliding ribosomes and phosphorylates MAP kinase kinases, leading to activation of the JNK and MAP kinase p38 pathways that promote programmed cell death (PubMed:32289254, PubMed:32610081). Less dangerous levels of ribosome collisions trigger the integrated stress response (ISR): MAP3K20 activates EIF2AK4/GCN2 independently of its protein-kinase activity, promoting EIF2AK4/GCN2-mediated phosphorylation of EIF2S1/eIF-2-alpha (PubMed:32610081). Also part of the stress-activated protein kinase signaling cascade triggering the NLRP1 inflammasome in response to UV-B irradiation: ribosome collisions activate MAP3K20, which directly phosphorylates NLRP1, leading to activation of the NLRP1 inflammasome and subsequent pyroptosis (PubMed:35857590). NLRP1 is also phosphorylated by MAP kinase p38 downstream of MAP3K20 (PubMed:35857590). Also acts as a histone kinase by phosphorylating histone H3 at 'Ser-28' (H3S28ph) (PubMed:15684425).
Isoform ZAKbeta
Isoform that lacks the C-terminal region that mediates ribosome-binding: does not act as a sensor of ribosome collisions in response to ribotoxic stress (PubMed:32289254, PubMed:32610081, PubMed:35857590). May act as an antagonist of isoform ZAKalpha: interacts with isoform ZAKalpha, leading to decrease the expression of isoform ZAKalpha (PubMed:27859413).
Involvement in disease
Split-foot malformation with mesoaxial polydactyly
SFMMP
An autosomal recessive disorder characterized by a split-foot defect, mesoaxial polydactyly, nail abnormalities of the hands, and sensorineural hearing loss.
None
The disease is caused by variants affecting the gene represented in this entry.
Myopathy, centronuclear, 6, with fiber-type disproportion
CNM6
A form of centronuclear myopathy, a congenital muscle disorder characterized by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life. Ptosis is a frequent clinical feature. The most prominent histopathologic features include high frequency of centrally located nuclei in muscle fibers not secondary to regeneration, radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers. CNM6 is an autosomal recessive, slowly progressive form with onset in infancy or early childhood.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Activated by phosphorylation by PKN1, followed by autophosphorylation on Thr-161 and Ser-165 (PubMed:12220515, PubMed:12761180, PubMed:15342622, PubMed:26999302). Autophosphorylation in response to ribotoxic stress promotes dissociation from colliding ribosomes and activation (PubMed:32289254, PubMed:32610081).
Sequence Similarities
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.
Tissue Specificity
Ubiquitously expressed. Isoform ZAKbeta is the predominant form in all tissues examined, except for liver, in which isoform ZAKalpha is more highly expressed.
Cellular localization
- Cytoplasm
- Nucleus
- Translocates to the nucleus upon ultraviolet B irradiation.
Alternative names
MLK7, MLTK, ZAK, HCCS4, MAP3K20, Mitogen-activated protein kinase kinase kinase 20, Human cervical cancer suppressor gene 4 protein, Leucine zipper- and sterile alpha motif-containing kinase, MLK-like mitogen-activated protein triple kinase, Mitogen-activated protein kinase kinase kinase MLT, Mixed lineage kinase 7, Mixed lineage kinase-related kinase, Sterile alpha motif- and leucine zipper-containing kinase AZK, HCCS-4, MLK-related kinase, MRK