Q9ESL4 · M3K20_MOUSE

  • Protein
    Mitogen-activated protein kinase kinase kinase 20
  • Gene
    Map3k20
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

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:11042189, PubMed:27598200).
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).
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:11042189).
Involved in stress associated with adrenergic stimulation: contributes to cardiac decompensation during periods of acute cardiac stress (By similarity).
May be involved in regulation of S and G2 cell cycle checkpoint by mediating phosphorylation of CHEK2 (By similarity).

Isoform ZAKalpha

Key component of the stress-activated protein kinase signaling cascade in response to ribotoxic stress or UV-B irradiation (PubMed:32289254).
Acts as the proximal sensor of ribosome collisions during the ribotoxic stress response (RSR) (PubMed:32289254).
Directly binds to the ribosome by inserting its flexible C-terminus into the ribosomal intersubunit space, thereby acting as a sentinel for colliding ribosomes (By similarity).
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 (By similarity).
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 (By similarity).
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 (By similarity).
Also acts as a histone kinase by phosphorylating histone H3 at 'Ser-28' (H3S28ph) (By similarity).

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. May act as an antagonist of isoform ZAKalpha: interacts with isoform ZAKalpha, leading to decrease the expression of isoform ZAKalpha.

Catalytic activity

Cofactor

Mg2+ (UniProtKB | Rhea| CHEBI:18420 )

Activity regulation

Activated in response to stress, such as ribosomal stress, osmotic shock and ionizing radiation. Activated by phosphorylation by PKN1, followed by autophosphorylation on Thr-161 and Ser-165.

Features

Showing features for binding site, active site.

TypeIDPosition(s)Description
Binding site22-30ATP (UniProtKB | ChEBI)
Binding site45ATP (UniProtKB | ChEBI)
Active site133Proton acceptor

GO annotations

AspectTerm
Cellular Componentcytoplasm
Cellular Componentcytosol
Cellular Componentnucleus
Molecular FunctionATP binding
Molecular FunctionJUN kinase kinase kinase activity
Molecular Functionmagnesium ion binding
Molecular FunctionMAP kinase kinase kinase activity
Molecular Functionprotein kinase activator activity
Molecular Functionprotein serine kinase activity
Molecular Functionprotein serine/threonine kinase activity
Molecular Functionribosome binding
Molecular Functionsmall ribosomal subunit rRNA binding
Biological Processcellular response to gamma radiation
Biological Processcellular response to UV-B
Biological Processcytoskeleton organization
Biological ProcessDNA damage checkpoint signaling
Biological Processembryonic digit morphogenesis
Biological ProcessGCN2-mediated signaling
Biological Processintracellular signal transduction
Biological ProcessJNK cascade
Biological Processlimb development
Biological Processp38MAPK cascade
Biological Processpositive regulation of apoptotic process
Biological Processpositive regulation of mitotic DNA damage checkpoint
Biological Processpositive regulation of programmed cell death
Biological Processprotein autophosphorylation
Biological Processprotein phosphorylation
Biological Processpyroptotic inflammatory response
Biological Processstress-activated MAPK cascade

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Mitogen-activated protein kinase kinase kinase 20
  • EC number
  • Alternative names
    • Leucine zipper- and sterile alpha motif kinase ZAK
    • 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-related kinase
      (MLK-related kinase
      ; MRK
      )
    • Sterile alpha motif- and leucine zipper-containing kinase AZK

Gene names

    • Name
      Map3k20
    • Synonyms
      Mltk
      , Zak

Organism names

  • Taxonomic identifier
  • Strains
    • C57BL/6J
    • FVB/N
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    Q9ESL4
  • Secondary accessions
    • Q3V1X8
    • Q8BR73
    • Q9ESL3

Proteomes

Organism-specific databases

Subcellular Location

Cytoplasm
Nucleus
Note: Appears to shuttle between nucleus and cytoplasm.

Keywords

Phenotypes & Variants

Disruption phenotype

Knockout results in fully penetrant lethality at 9.5 dpc due to severe cardiac edema and growth retardation (PubMed:26755636).
Embryos show polydactyly of the feet (PubMed:26755636).
Defects in stress-activated protein kinase signaling cascade in response to ribotoxic stress, leading to impaired activation of the JNK and MAP kinase p38 pathways (PubMed:27598200).

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis45Loss of kinase activity.
Mutagenesis368Causes a split-hand/split-foot phenotype in knockin mice. Gain-of-function mutant that cases a constitutive ribotoxic stress response (RSR).

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 32 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

Chemistry

PTM/Processing

Features

Showing features for initiator methionine, modified residue, chain.

TypeIDPosition(s)Description
Initiator methionine1Removed
Modified residue2N-acetylserine
Modified residue2Phosphoserine
ChainPRO_00000863392-802Mitogen-activated protein kinase kinase kinase 20
Modified residue3Phosphoserine
Modified residue7Phosphoserine
Modified residue161Phosphothreonine; by autocatalysis
Modified residue165Phosphoserine; by autocatalysis
Modified residue275Phosphoserine
Modified residue302Phosphoserine
Modified residue434In isoform Q9ESL4-2; Phosphoserine
Modified residue453In isoform Q9ESL4-2; Phosphoserine
Modified residue567Phosphoserine
Modified residue586Phosphothreonine
Modified residue587Phosphoserine
Modified residue593Phosphoserine
Modified residue599Phosphoserine
Modified residue628Phosphothreonine
Modified residue634Phosphoserine
Modified residue638Phosphoserine
Modified residue649Phosphoserine
Modified residue650Phosphoserine
Modified residue661Phosphoserine
Modified residue685Phosphoserine
Modified residue720Phosphoserine
Modified residue727Phosphoserine
Modified residue733Phosphoserine
Modified residue744Phosphothreonine

Post-translational modification

Activated by phosphorylation by PKN1, followed by autophosphorylation on Thr-161 and Ser-165 (By similarity).
Autophosphorylation in response to ribotoxic stress promotes dissociation from colliding ribosomes and activation (By similarity).

Keywords

Proteomic databases

PTM databases

Expression

Developmental stage

Mainly expressed in heart and developing limbs.

Gene expression databases

Interaction

Subunit

Homodimer (PubMed:11042189).
Interacts with ZNF33A (By similarity).
Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, MAP3K20 and MAP2K3 (By similarity).
Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and MAP3K20 (By similarity).
Interacts with EIF2AK4/GCN2; promoting EIF2AK4/GCN2 kinase activity (By similarity).

Isoform ZAKalpha

Interacts with isoform ZAKbeta.

Isoform ZAKbeta

Interacts with isoform ZAKalpha.

Protein-protein interaction databases

Miscellaneous

Structure

Family & Domains

Features

Showing features for domain, region, compositional bias.

TypeIDPosition(s)Description
Domain16-277Protein kinase
Region287-308Leucine-zipper
Domain339-410SAM
Compositional bias624-668Polar residues
Region624-802Disordered
Region670-713Sensing domain (S)
Compositional bias680-708Polar residues
Compositional bias730-744Basic and acidic residues
Compositional bias755-802Basic and acidic residues
Region776-802C-terminal domain (CTD)

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).

Sequence similarities

Phylogenomic databases

Family and domain databases

Sequence & Isoforms

Align isoforms (3)
  • Sequence status
    Complete

This entry describes 3 isoforms produced by Alternative splicing.

Q9ESL4-1

This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

  • Name
    ZAKalpha
  • Synonyms
    Alpha
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Length
    802
  • Mass (Da)
    91,720
  • Last updated
    2001-03-01 v1
  • Checksum
    D431DF8F312A43CC
MSSLGASFVQIKFDDLQFFENCGGGSFGSVYRAKWISQDKEVAVKKLLKIEKEAEILSVLSHRNIIQFYGVILEPPNYGIVTEYASLGSLYDYINSNRSEEMDMEHIMTWATDVAKGMHYLHMEAPVKVIHRDLKSRNVVIAADGVLKICDFGASRFHNHTTHMSLVGTFPWMAPEVIQSLPVSETCDTYSYGVVLWEMLTREVPFKGLEGLQVAWLVVEKNERLTIPSSCPRSFAELLHQCWEADAKKRPSFKQIISILESMSNDTNLPDQCNSFLHNKAEWRCEIEATLERLKKLERDLSFKEQELKERERRLKMWEQKLTEQSNTPLLPSFEIGAWTEDDVYFWVQQLVRKGESSVEMSGYASLFKENNITGKRLLLLEEEDLKDMGIVSKGHIIHFKSAIEKLTHDYLNLFHFPPLIKDSGGEPEENEEKIVNLELVFGFHLKPGTGPQDCKWKMYMEMDGDEVAITYIKDVTFNTSLPDAEILKMTKPPFVMEKWIVGIAEDQTVECTVTYENDVRTPKLTKHVHSIQWDRTKPQDEVKAVQLAIQTLFSSSEGNPGSRSDSSADCQWLDTLRMRQIASHTSLQRSQSNPILGSPFFPYFANQDSYAAAVRRTQTPVKYQQITPSINPSRSSSPTQYGLSRNFSSLNLSSRDSGFSSLNDSSSERGRYSDRSRNKYYRGSVSLNSSPKGRYGGKSQHSTPSRERYSGKFYRLPQSALNTHQSPDFKRSPNDHDRRVPRTIPGMPLHPETASKAGEEESRVSEGGWTKVEYRKKTHRQLSAKTSKERTRGNYRGRRNF

Q9ESL4-2

  • Name
    ZAKbeta
  • Synonyms
    Beta
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical
    • 332-454: PSFEIGAWTEDDVYFWVQQLVRKGESSVEMSGYASLFKENNITGKRLLLLEEEDLKDMGIVSKGHIIHFKSAIEKLTHDYLNLFHFPPLIKDSGGEPEENEEKIVNLELVFGFHLKPGTGPQD → LPLSARMSEESYFESKTEESNSAEMSCQITAASNGEGHGMNPGLQAMMLMGFGDVFSMNKAGAVLHSGMQINMQAKQNSSKTTCKRRGKKVNMALGFSDFDLSEGDDDDHDGDDAENDVDNSE
    • 455-802: Missing

Q9ESL4-3

  • Name
    3
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical

Computationally mapped potential isoform sequences

There is 1 potential isoform mapped to this entry

View all
EntryEntry nameGene nameLength
A2ASW6A2ASW6_MOUSEMap3k2074

Features

Showing features for sequence conflict, alternative sequence, compositional bias.

TypeIDPosition(s)Description
Sequence conflict171in Ref. 2; BAC32371
Alternative sequenceVSP_051747285-289in isoform 3
Alternative sequenceVSP_051748290-802in isoform 3
Alternative sequenceVSP_051745332-454in isoform ZAKbeta
Alternative sequenceVSP_051746455-802in isoform ZAKbeta
Compositional bias624-668Polar residues
Compositional bias680-708Polar residues
Compositional bias730-744Basic and acidic residues
Compositional bias755-802Basic and acidic residues

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AB049731
EMBL· GenBank· DDBJ
BAB16442.1
EMBL· GenBank· DDBJ
mRNA
AB049732
EMBL· GenBank· DDBJ
BAB16443.1
EMBL· GenBank· DDBJ
mRNA
AK045444
EMBL· GenBank· DDBJ
BAC32371.1
EMBL· GenBank· DDBJ
mRNA
AK132186
EMBL· GenBank· DDBJ
BAE21021.1
EMBL· GenBank· DDBJ
mRNA
BC023718
EMBL· GenBank· DDBJ
AAH23718.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

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