MAP2K5 + MAP3K3 complex
MAP2K5 + MAP3K3 complex: Human MAP2K5 (MEK5)-MAP3K3 (MEKK3) Phox domain complex
PDB Code: 2O2V
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.
MEKK3 the upstream activator of MEK5 and is a key molecule regulating cell proliferation. In addition MEKK3 plays an important role in the adaptation to different osmotic conditions. MEKK3 signaling is essential for cardiac hypertrophy and heart development by controlling the functions of the two key cardiac transcription factors NFAT and MEF2C. Transgenic mice with a cardiac specific expression of active MEKK3 suffer from cardiac hypertrophy and sudden death.
Elevated MEKK3 protein levels have been found in many human breast and ovarian cancers resulting in increased NFkappaB activity and subsequent expression of cell survival factors. This altered expression profile ultimately contributes to resistance of cancer cells overexpressing MEKK3 to apoptosis.
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