MEK1 acts as a convergence point for the multiple protein kinases involved in MAPK activation Specific protein kinases transfer a phosphate group from a donor such as ATP to amino acid acceptors in proteins, while protein phosphatases remove the phosphate groups that have been attached by protein kinases.
MEK act as substrates for several protein kinases including the Rafs (c-, A- and B-), Mos, Tpl-2, and MEKK1. Raf and MEKK mainly phosphorylate MEKs at serine residues (218 and 222 in rat MEK1). Raf and MAPK/extracellular signal-regulated kinase kinase (MEKK) independently phosphorylate and activate MEK-1, establishing a protein kinase signaling cascade whose activity is controlled by G-protein linked effectors and tyrosine kinases. Raf phosphorylation is reported to increases recombinant MEK1 activity two-fold, while MEKK phosphorylation of recombinant MEK1 increases MEK1 activity five-fold.
MAPK phosphorylates MEK1 at sites (threonine) different than those phosphorylated by Raf and MEKK (serine and tyrosine)[s4]. MEK1 acts as a convergence point for the multiple protein kinases involved in MAPK activation.[s7] MEKK and Raf regulate MEK-1 activity by phosphorylation of common residues and thus, two independent protein kinases converge at MEK-1 to regulate the activity of MAPK. Phosphorylation of MEK-1 by MAPK does not affect MEK-1 kinase activity. Constitutive activation of MEKs depends on introduction of acidic residues and truncation of an alpha-helical region in the N-terminal domain. Mutation of the serine residues to alanine generates dominant-negative proteins that have been used to determine requirement for the ERK pathway. The major site of MAPK phosphorylation in MEK-1 is threonine 292, and site-directed mutagenesis of threonine 292 to alanine eliminates 90% of MAPK catalyzed phosphorylation of MEK-1 yet does not inhibit MEK-1 autoactivation.
Two related genes encode MEK1 and MEK2 which differ in their binding to ERKs. MEKs do not phosphorylate either SAPK or p38 MAPK. [ut]
The Raf/mitogen-activated protein kinase (MAPK/ERK) kinase, (MEK)/mitogen-activated protein kinase (MAPK), and the phosphatidylinositide-3-OH kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt pathways play central roles in the regulation of cell survival and proliferation.
MEK-1 is a dual threonine and tyrosine recognition kinase that phosphorylates and activates mitogen-activated protein kinase (MAPK). MEK-1 is in turn activated by phosphorylation.