MAP3K4

Protein identityUniProt · HPA

UniProt accession

Q9Y6R4

Gene

MAP3K4

Ensembl

ENSG00000085511

Chromosome

6

Canonical length

1608 aa

Protein class

Cancer-related genes, Enzymes, Predicted intracellular proteins

Subcellular location

Cytosol

Quaternary structure

Homodimer

OverviewNCBI Gene

The central core of each mitogen-activated protein kinase (MAPK) pathway is a conserved cascade of 3 protein kinases: an activated MAPK kinase kinase (MAPKKK) phosphorylates and activates a specific MAPK kinase (MAPKK), which then activates a specific MAPK. While the ERK MAPKs are activated by mitogenic stimulation, the CSBP2 and JNK MAPKs are activated by environmental stresses such as osmotic shock, UV irradiation, wound stress, and inflammatory factors. This gene encodes a MAPKKK, the MEKK4 protein, also called MTK1. This protein contains a protein kinase catalytic domain at the C terminus. The N-terminal nonkinase domain may contain a regulatory domain. Expression of MEKK4 in mammalian cells activated the CSBP2 and JNK MAPK pathways, but not the ERK pathway. In vitro kinase studies indicated that recombinant MEKK4 can specifically phosphorylate and activate PRKMK6 and SERK1, MAPKKs that activate CSBP2 and JNK, respectively but cannot phosphorylate PRKMK1, an MAPKK that activates ERKs. MEKK4 is a major mediator of environmental stresses that activate the CSBP2 MAPK pathway, and a minor mediator of the JNK pathway. Several alternatively spliced transcripts encoding distinct isoforms have been described. [provided by RefSeq, May 2014]

Canonical amino-acid sequenceUniProt

1608 residues, UniProt reviewed canonical sequence.

>Q9Y6R4|MAP3K4
     1  MREAAAALVP PPAFAVTPAA AMEEPPPPPP PPPPPPEPET ESEPECCLAA RQEGTLGDSA
    61  CKSPESDLED FSDETNTENL YGTSPPSTPR QMKRMSTKHQ RNNVGRPASR SNLKEKMNAP
   121  NQPPHKDTGK TVENVEEYSY KQEKKIRAAL RTTERDRKKN VQCSFMLDSV GGSLPKKSIP
   181  DVDLNKPYLS LGCSNAKLPV SVPMPIARPA RQTSRTDCPA DRLKFFETLR LLLKLTSVSK
   241  KKDREQRGQE NTSGFWLNRS NELIWLELQA WHAGRTINDQ DFFLYTARQA IPDIINEILT
   301  FKVDYGSFAF VRDRAGFNGT SVEGQCKATP GTKIVGYSTH HEHLQRQRVS FEQVKRIMEL
   361  LEYIEALYPS LQALQKDYEK YAAKDFQDRV QALCLWLNIT KDLNQKLRIM GTVLGIKNLS
   421  DIGWPVFEIP SPRPSKGNEP EYEGDDTEGE LKELESSTDE SEEEQISDPR VPEIRQPIDN
   481  SFDIQSRDCI SKKLERLESE DDSLGWGAPD WSTEAGFSRH CLTSIYRPFV DKALKQMGLR
   541  KLILRLHKLM DGSLQRARIA LVKNDRPVEF SEFPDPMWGS DYVQLSRTPP SSEEKCSAVS
   601  WEELKAMDLP SFEPAFLVLC RVLLNVIHEC LKLRLEQRPA GEPSLLSIKQ LVRECKEVLK
   661  GGLLMKQYYQ FMLQEVLEDL EKPDCNIDAF EEDLHKMLMV YFDYMRSWIQ MLQQLPQASH
   721  SLKNLLEEEW NFTKEITHYI RGGEAQAGKL FCDIAGMLLK STGSFLEFGL QESCAEFWTS
   781  ADDSSASDEI RRSVIEISRA LKELFHEARE RASKALGFAK MLRKDLEIAA EFRLSAPVRD
   841  LLDVLKSKQY VKVQIPGLEN LQMFVPDTLA EEKSIILQLL NAAAGKDCSK DSDDVLIDAY
   901  LLLTKHGDRA RDSEDSWGTW EAQPVKVVPQ VETVDTLRSM QVDNLLLVVM QSAHLTIQRK
   961  AFQQSIEGLM TLCQEQTSSQ PVIAKALQQL KNDALELCNR ISNAIDRVDH MFTSEFDAEV
  1021  DESESVTLQQ YYREAMIQGY NFGFEYHKEV VRLMSGEFRQ KIGDKYISFA RKWMNYVLTK
  1081  CESGRGTRPR WATQGFDFLQ AIEPAFISAL PEDDFLSLQA LMNECIGHVI GKPHSPVTGL
  1141  YLAIHRNSPR PMKVPRCHSD PPNPHLIIPT PEGFSTRSMP SDARSHGSPA AAAAAAAAAV
  1201  AASRPSPSGG DSVLPKSISS AHDTRGSSVP ENDRLASIAA ELQFRSLSRH SSPTEERDEP
  1261  AYPRGDSSGS TRRSWELRTL ISQSKDTASK LGPIEAIQKS VRLFEEKRYR EMRRKNIIGQ
  1321  VCDTPKSYDN VMHVGLRKVT FKWQRGNKIG EGQYGKVYTC ISVDTGELMA MKEIRFQPND
  1381  HKTIKETADE LKIFEGIKHP NLVRYFGVEL HREEMYIFME YCDEGTLEEV SRLGLQEHVI
  1441  RLYSKQITIA INVLHEHGIV HRDIKGANIF LTSSGLIKLG DFGCSVKLKN NAQTMPGEVN
  1501  STLGTAAYMA PEVITRAKGE GHGRAADIWS LGCVVIEMVT GKRPWHEYEH NFQIMYKVGM
  1561  GHKPPIPERL SPEGKDFLSH CLESDPKMRW TASQLLDHSF VKVCTDEE

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against MAP3K4 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Intracellular

Secreted

No

Transmembrane segments

0

Mean surface accessibility (rSASA)

0.41

Highest tissue expression

10 nTPM

Expression across tissuesHPA

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.18

gnomAD pLI

1

gnomAD missense Z

2.87

DepMap mean gene effect

-0.01

DepMap dependency class

selective

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 4% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• chorionic trophoblast cell differentiation
• intracellular signal transduction
• male germ-line sex determination
• MAPK cascade
• p38MAPK cascade
• placenta development
• positive regulation of JUN kinase activity
• positive regulation of p38MAPK cascade
• positive regulation of telomere maintenance
• regulation of gene expression
• response to UV-C

Molecular functions

• ATP binding
• MAP kinase kinase kinase activity
• metal ion binding
• protein serine kinase activity

Cellular components

• cytoplasm
• perinuclear region of cytoplasm

Protein domainsUniProt · Pfam · InterPro

• Protein kinase domain
• Serine/threonine-protein kinase, active site
• Protein kinase-like domain superfamily
• Protein kinase, ATP binding site
• Mitogen-activated protein kinase kinase kinase
• Protein kinase domain
• Mitogen-activated protein kinase kinase kinase, N-terminal
• MEKK4 N-terminal

KeywordsUniProt

• ATP-binding
• Cytoplasm
• Kinase
• Magnesium
• Metal-binding
• Nucleotide-binding
• Phosphoprotein
• Serine/threonine-protein kinase
• Transferase

InteractionsUniProt · HPA

Protein binding partners of MAP3K4 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• AXIN1
• CDC42
• DIXDC1
• GADD45
• MAP2K6
• SH3KBP1
• TRAF4
• ZFP36
• RIPK2
• ACTB
• GADD45A
• GADD45B
• GADD45G