MAP2K5 + MAP3K2 complex
MAP2K5 + MAP3K2 complex: Human MAP2K5 (MEK5)-MAP3K2 (MEKK2) Phox domain complex
PDB Code: 2NPT
PB1 domains are scaffold modules that interact with each other in a front-to-back mode to arrange heterodimers or homooligomers of signaling molecules. The different PB1 domain adaptors provide specificity for PB1 domain containing kinases to ensure an effective transmission of cellular signals. The PB1 domain of MEK5 represents a stable scaffold that forms a functional signaling complex which results in the specific activation of ERK5.
Overexpression of MEK5 has been linked to tumor metastasis and a poor survival rate of prostate cancer patients and MEK5 is often constitutively activated in human prostate cancer. Suppression of signaling trough inhibition of MEK5 has been suggested as a potential target for cancer therapy.
MEKK2 the upstream activator of MEK5 is a key molecule in T-cell receptor signaling and plays an important role in immune synapse formation during antigenic stimulation . In addition, MEKK2 is a major sensor for Toll like receptors signals and has also been suggested to play a role in the regulation of cytokine gene expression in mast cells.
MEKK2 contains an atypical PB1 domain which lacks key residues in the acidic cluster and interaction studies together with site directed mutagenesis experiments have shown that the PB1 domain of MEKK2 uses the front basic cluster to bind to the MEK5 rear end acidic cluster. Interactions mediated through MEK5 PB1 domain are required for the formation of a functional MEKK2-MEK5-ERK5 signaling complex and the activation of ERK5.
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