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Overview

Uniprot ID	P52564
Protein Name	Dual specificity mitogen-activated protein kinase kinase 6
Gene Name	MAP2K6
Organism	Homo sapiens

Kla Sites from experimental identification

Position	Flanking peptide
14	KKRNPGLKIPKEAFE
17	NPGLKIPKEAFEQPQ

Function

Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases

Protein Sequence

10 MSQSKGKKRN 20 PGLKIPKEAF 30 EQPQTSSTPP 40 RDLDSKACIS 50 IGNQNFEVKA 60 DDLEPIMELG 70 RGAYGVVEKM 80 RHVPSGQIMA 90 VKRIRATVNS 100 QEQKRLLMDL 110 DISMRTVDCP 120 FTVTFYGALF 130 REGDVWICME 140 LMDTSLDKFY 150 KQVIDKGQTI 160 PEDILGKIAV 170 SIVKALEHLH 180 SKLSVIHRDV 190 KPSNVLINAL 200 GQVKMCDFGI 210 SGYLVDSVAK 220 TIDAGCKPYM 230 APERINPELN 240 QKGYSVKSDI 250 WSLGITMIEL 260 AILRFPYDSW 270 GTPFQQLKQV 280 VEEPSPQLPA 290 DKFSAEFVDF 300 TSQCLKKNSK 310 ERPTYPELMQ 320 HPFFTLHESK 330 GTDVASFVKL ILGD

Gene Ontology

Classification	GO ID	Description
Cellular Component	GO:0005737	cytoplasm
Biological Process	GO:0007165	signal transduction
Biological Process	GO:0042770	signal transduction in response to DNA damage
Biological Process	GO:0051403	stress-activated MAPK cascade
Biological Process	GO:0031098	stress-activated protein kinase signaling cascade
Cellular Component	GO:0005856	cytoskeleton
Cellular Component	GO:0005829	cytosol
Cellular Component	GO:0005654	nucleoplasm
Molecular Function	GO:0005524	ATP binding
Molecular Function	GO:0042802	identical protein binding
Molecular Function	GO:0004708	MAP kinase kinase activity
Molecular Function	GO:0019901	protein kinase binding
Molecular Function	GO:0106310	protein serine kinase activity
Molecular Function	GO:0004674	protein serine/threonine kinase activity
Molecular Function	GO:0004713	protein tyrosine kinase activity
Biological Process	GO:0006915	apoptotic process
Biological Process	GO:0060348	bone development
Biological Process	GO:0090398	cellular senescence
Biological Process	GO:0006351	DNA-templated transcription
Biological Process	GO:0000165	MAPK cascade
Biological Process	GO:0120163	negative regulation of cold-induced thermogenesis
Biological Process	GO:0035872	nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway
Biological Process	GO:0001649	osteoblast differentiation
Biological Process	GO:0038066	p38MAPK cascade
Biological Process	GO:0051726	regulation of cell cycle
Biological Process	GO:1901796	regulation of signal transduction by p53 class mediator

Reference

[1] Yang D, Yin J, Shan L, Yi X, Zhang W et al.. Identification of lysine-lactylated substrates in gastric cancer cells.. iScience 25(7):104630. 2022 Jul 15. PMID: 35800753.

[2] Yang Z, Yan C, Ma J, Peng P, Ren X et al.. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma.. Nat Metab 5(1):61-79. 2023 Jan. PMID: 36593272.

[3] Shi CM, Wang QC, Li XL, Yang YH, Tang XY et al.. Global Profiling of Protein Lactylation in Human Hippocampi.. Proteomics Clin Appl 19(2):e202400061. 2025 Mar. PMID: 39610256.

[4] He J, Lai T, Zhou Z, Yang H, Lei Z et al.. Multiomics profiling reveals the involvement of protein lactylation in nonhomologous end joining pathway conferring radioresistance in lung adenocarcinoma cell.. Sci Rep 15(1):24651. 2025 Jul 9. PMID: 40634431.