MAP2K4

Description

The MAP2K4 (mitogen-activated protein kinase kinase 4) is a protein-coding gene located on chromosome 17.

MAP2K4, also known as Dual-specificity mitogen-activated protein kinase kinase 4, is an enzyme encoded by the MAP2K4 gene in humans. It belongs to the Ser/Thr protein kinase family and acts as a dual-specificity kinase, phosphorylating MAP kinases in response to various environmental stresses or mitogenic stimuli. MAP2K4 phosphorylates MAPK8/JNK1, MAPK9/JNK2, and MAPK14/p38, but not MAPK1/ERK2 or MAPK3/ERK1. Structurally, it contains a kinase domain that is activated by phosphorylation from MAP3K1 (MEKK1). MAP2K4 undergoes phosphorylation and ubiquitination at multiple amino acid sites. Studies using Map2k4 knockout mice revealed embryonic lethality, impaired hepatogenesis, and defective liver formation. Analysis of chimeric mice indicated a role for Map2k4 in T cell cytokine production and proliferation. Map2k4-deficient chimeric mice frequently develop lymphadenopathy. Notably, MAP2K4 is altered in 1.97% of all human cancers.

MAP2K4 is a dual specificity protein kinase that acts as an essential component of the MAP kinase signal transduction pathway. It is crucial for the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway, and is one of the only known kinases to directly activate the JNKs, along with MAP2K7/MKK7. Both MAP2K4/MKK4 and MAP2K7/MKK7 activate JNKs by phosphorylation, but they exhibit a preference for different phosphorylation sites within the Thr-Pro-Tyr motif. MAP2K4 favors phosphorylation of the Tyr residue, while MAP2K7/MKK7 favors the Thr residue. Phosphorylation of the Thr residue by MAP2K7/MKK7 appears to be a prerequisite for JNK activation, particularly in response to pro-inflammatory cytokines. However, other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7, leading to synergistic phosphorylation of JNKs. MAP2K4 is essential for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway also plays a role in mitochondrial death signaling pathways, including the release of cytochrome c, ultimately leading to apoptosis. While MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs, including MAPK11, MAPK12, MAPK13, and MAPK14.

MAP2K4 is also known as JNKK, JNKK1, MAPKK4, MEK4, MKK4, PRKMK4, SAPKK-1, SAPKK1, SEK1, SERK1, SKK1.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing