MAP3K3: Human MAP/ ERK kinase 3, Phox/ PB1 domain
PDB Code: 2C60
MEKK3 (MAP3K3) belongs to the Mekk/Ste11 family of serine/threonine kinases and is a member of the MAP-kinase signaling cascade that activates and phosphorylates the kinase MEK5 in response to growth factors, oxidative stress, and hyperosmotic conditions. MEKK3 directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 . Moreover, MEKK3 is crucial for IL1-R and TLR4 signaling through the IKK-NF?B and JNK-p38 MAPK pathways.
Disruption of the mouse gene showed that MEKK3 plays a crucial role in angiogenesis. Mekk3 -/- embryos died at embryonic day 11 (E11) and showed severe disruption of blood vessel development and the structural integrity of the yolk sac. In addition, angiogenesis was blocked at approximately E9.5. MEKK3 was also shown to activate myocyte-specific enhancer factor 2C which is a crucial transcription factor for early embryonic cardiovascular development through the p38 mitogen-activated protein kinase cascade. In addition, active MEKK3 has been shown to be capable of activating calcineurin/NFAT signalling in cardiac myocytes and reprogramming cardiac gene expression.
The protein- protein interaction domain PB1/phox domain is found in proteins of yeast, plants, and metazoans and was first identified in p67 phox , involved in activation of phagocyte NADPH oxidase (Phox-domain). The PB1/Phox domain of MEKK3 is encoded within the N-terminus of the protein and has been shown to mediate interaction with the PB1 domains of MEK5 by forming heterodimers. Functional importance of this protein interaction domain has been demonstrated by transfection experiments which showed that expression of MEKK3 PB1 domain had a dominant negative effect on ERK5 activation.

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