MEKK1 or MEK kinase, is a serine/threonine kinase that is downstream of mitogenic and metabolic stimuli, including insulin and many growth factors. MEKK1 functions not only as an upstream activator of ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/ERK2 activity by ubiquitination and degradation. MEKK1 -/- embryonic stem cells from mice show loss or altered responses of JNK to microtubule disruption and cold stress. Furthermore, activation of JNK is lost and that of ERK is diminished in response to hyperosmolarity and serum factors in MEKK1 -/- cells.
Science (New York, N.Y.), 282(5395), 1911-1914 (1998-12-04)
Targeted disruption of the gene encoding MEK kinase 1 (MEKK1), a mitogen-activated protein kinase (MAPK) kinase kinase, defined its function in the regulation of MAPK pathways and cell survival. MEKK1(-/-) embryonic stem cells from mice had lost or altered responses
ERK1/2 MAP kinases are important regulators in cellular signaling, whose activity is normally reversibly regulated by threonine-tyrosine phosphorylation. In contrast, we have found that stress-induced ERK1/2 activity is downregulated by ubiquitin/proteasome-mediated degradation of ERK1/2. The PHD domain of MEKK1, a
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