Recombinant Mouse Dual specificity mitogen-activated protein kinase kinase 4 (Map2k4)

Function

Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to pro-inflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14

Subcellular Location

Cytoplasm; Nucleus

Tissue Specificity

Strong expression is detected in most of the central nervous system and in liver and thymus during early stages of development. While expression in nervous system increases over time, expression in fetal liver and thymus gradually decreases as embryogenesis proceeds. High level of expression in the central nervous system persists throughout postnatal development and remained at a stable level in adult brain

Subunit

Interacts with SPAG9. Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14 (By similarity). Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3 (By similarity)

• Sanchez I. et al. Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. — Nature (1994)
• Zon L.I. et al. PubMed: CI-C3OGC4PD4GM46 (DEC-)
• Swat W. et al. SEK1/MKK4 is required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development. — Immunity (1998)
• Tournier C. et al. The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases. — Mol. Cell. Biol. (1999)
• Lee J.K. et al. Dynamic expression of SEK1 suggests multiple roles of the gene during embryogenesis and in adult brain of mice. — Brain Res. Mol. Brain Res. (1999)
• Tournier C. et al. MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. — Genes Dev. (2001)
• Tu Z. et al. A subdomain of MEKK1 that is critical for binding to MKK4. — Cell. Signal. (2003)
• Kishimoto H. et al. Different properties of SEK1 and MKK7 in dual phosphorylation of stress-induced activated protein kinase SAPK/JNK in embryonic stem cells. — J. Biol. Chem. (2003)