MAP3K1


Mitogen-activated protein kinase kinase kinase 1 is an enzyme that in humans is encoded by the MAP3K1 gene.

Function

MAP3K1 is a serine/threonine kinase that performs a pivotal role in a network of phosphorylating kinase enzymes integrating cellular receptor responses to a number of mitogenic and metabolic stimuli, including: TNF receptor superfamily, T-cell receptor, Epidermal growth factor receptor , and TGF beta receptor. Mitogen-activated protein kinase kinases are substrates for direct phosphorylation by the MAP3K1 protein kinase. Mouse genetics has revealed that MAP3K1 is important in: embryonic development, tumorigenesis, cell growth, cell migration, cytokine production, and humoral immunity. MAP3K1 has been identified by GWAS in breast cancer

Structure

MAP3K1 contains a protein kinase domain as well as PHD finger and scaffold protein regions that mediate protein–protein interactions.

Genetic analyses in murine and avian models

MAP3K1 is highly conserved in Euteleostomi. The recessive lidgap-Gates mutation identified on the SELH/Bc mouse strain causes the same open-eyelids-at-birth mutational phenotype as the gene knockout mutations of the mouse MAP3K1 homolog and also co-maps to distal Chromosome 13. MAP3K1 has been analysed genetically by targeted mutagenesis using transgenic mice, embryonic stem cells, and the DT40 cell line to identify genetic traits.
Map3k1 mutantSpeciesGenetic modelReferences
Deletion amino-terminusMus musculusTransgenic mouse and embryonic stem cells
Deletion kinase domainMus musculusTransgenic mouse and embryonic stem cells
Point mutations PHD fingerMus musculusTransgenic mouse and embryonic stem cells
T cell-specific deletionMus musculusTransgenic mouse
Deletion carboxyl-terminusGallus gallus domesticusLymphoblast cell line

Activation and deactivation

MAP3K1 contains multiple sites that are phosphorylated and ubiquitinated. Cytokine signaling through MAP3K1 utilises two-stage cell signaling to recruit the signal transduction mechanism to cytokine receptors and then release these components from the cellular membrane.

Disease and therapeutic targeting

MAP3K1 is mutated in 3.05% of all human cancers. MAP3K1 is a breast cancer susceptibility allele, acute respiratory distress syndrome associated allele, Langerhans cell histiocytosis gene, and 46,XY disorders of sex development linked gene. E6201 is an enzyme inhibitor of MAP3K1 that shows cross-specificity with MAP2K1.

Interaction partners

MAP3K1 has been shown to interact with a number of proteins, including: