Mixed lineage kinase 3 (MLK3) is a serine/threonine kinase that has an amino-terminal SH3 domain followed by the kinase domain and two leucine zippers, a cdc42/Rac1 binding (CRIB) domain and several other domains/motifs at the carboxy-terminal region. CRIB triggers the dimerization of MLK3 via its tandem leucine zippers, followed by the intramolecular phosphorylation and subsequent activation of MLK3. Autophosphorylation of Thr277 and Ser281 is essential for MLK3 kinase activity. Ser281 is also phosphorylated by HPK in an in vitro kinase assay. MLK3 functions as a MAPKKK of the SAPK/JNK stress pathway by directly phosphorylating SEK1/MKK4 and MKK7, although it is controversial whether MLK3 is involved in p38 stress pathway activation. MLK3 also functions as an IkappaB kinase and mediates the activation of the transcriptional factor NF-kappaB stimulated by CD3/CD28, suggesting a role for MLK3 in immune and inflammatory responses.
