- MEK1/2 (also known as MAP2K1/2 or MAPK/ERK kinase 1/2) are dual-specificity protein kinases that play a central role in the MAP kinase/ERK signaling cascade, one of the most well-studied cellular signaling pathways in biology.
- These enzymes are crucial intermediates in the RAS-RAF-MEK-ERK pathway, which transmits signals from cell surface receptors to regulate various cellular processes. MEK1 and MEK2 share approximately 85% sequence identity and have similar functions, though they are encoded by different genes. They are characterized by their unique ability to phosphorylate both threonine and tyrosine residues on their substrates, particularly ERK1/2.
- MEK1/2 are activated through phosphorylation by upstream kinases, primarily RAF proteins. Once activated, MEK1/2 specifically phosphorylate ERK1/2 at two sites: threonine 202/185 and tyrosine 204/187. This dual phosphorylation is required for full activation of ERK1/2, which then proceed to phosphorylate numerous downstream substrates involved in cell proliferation, differentiation, and survival.
- The regulation of MEK1/2 is tightly controlled through various mechanisms, including phosphorylation, protein-protein interactions, and spatial organization within the cell. Their activity is essential for normal cellular function, but dysregulation of MEK1/2 signaling has been implicated in various diseases, particularly cancer. Mutations that lead to constitutive activation of MEK1/2 are found in several types of human cancers.
- Due to their critical role in cancer development and progression, MEK1/2 have become important therapeutic targets. Several MEK inhibitors have been developed and approved for clinical use, particularly in treating melanoma and other cancers with BRAF mutations. These inhibitors work by blocking MEK1/2 activity, thereby preventing the overactivation of ERK1/2 and reducing cancer cell proliferation.
- The structure of MEK1/2 includes an N-terminal regulatory region, a kinase domain, and a C-terminal region. The regulatory region contains several phosphorylation sites and protein interaction motifs that modulate MEK1/2 activity. The kinase domain possesses the catalytic activity necessary for phosphorylating ERK1/2, while the C-terminal region contains additional regulatory elements.
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