A Divergence in the MAP Kinase Regulatory Network Defined by MEK Kinase and Raf

Abstract

Mitogen-activated protein kinases (MAPKs) are rapidly phosphorylated and activated in response to various extracellular stimuli in many different cell types. Such regulation of MAPK results from sequential activation of a series of protein kinases. The kinases that phosphorylate MAPKs, the MAP kinase kinases (MEKs) are also activated by phosphorylation. MEKs are related in sequence to the yeast protein kinases Byr1 (from Schizosaccharomyces pombe) and Ste7 (from Saccharomyces cerevisiae), which function in the pheromone-induced signaling pathway that results in mating. Byr1 and Ste7 are in turn regulated by the protein kinases Byr2 and Ste11. The amino acid sequence of the mouse homolog of Byr2 and Ste11, denoted MEKK (MEK kinase), was elucidated from a complementary DNA sequence encoding a protein of 672 amino acid residues (73 kilodaltons). MEKK was expressed in all mouse tissues tested, and it phosphorylated and activated MEK. Phosphorylation and activation of MEK by MEKK was independent of Raf, a growth factor-regulated protein kinase that also phosphorylates MEK. Thus, MEKK and Raf converge at MEK in the protein kinase network mediating the activation of MAPKs by hormones, growth factors, and neurotransmitters.

c-Jun, at the crossroad of the signaling network

“…MAP3K1 was originally identified as a mammalian homolog of the yeast MEK kinases, Byr2 and Ste11, involved in pheromone-induced mating (Lange-Carter et al, 1993). Although initially considered as an upstream activator of ERK, it soon became clear that MAP3K1 preferentially activates the JNK pathway, by interacting with and phosphorylating the JNK activator, MKK4 (Minden et al, 1994;Yan et al, 1994;Lin et al, 1995;Xia et al, 1998).…”

Signaling by dual specificity kinases

“…However, it is worth noting that MKK1/2 can also be activated through a Ras-Raf independent pathway. MKK1/2 can be phosphorylated by other dual speci®city kinase kinase such as cMOS (Nebreda et al, 1993;Shibuya and Rudersman, 1993;Posada et al, 1993) or MEKK1 (Lange-Carter et al, 1993). Phosphorylation of MKK1 by cMOS has been observed only in Xenopus oocytes suggesting cell-type speci®city of MOS-MKK1 interaction.…”

Differential phosphorylation of mitogen-activated protein kinase families by epidermal growth factor and ultraviolet B irradiation in SV40-transformed human keratinocytes

“…MAP kinase families, that include extracellular regulated kinase (ERK) 1, 2, p38, and stress-activated protein kinase/c-Jun N-terminal kinase (JNK), are essential signal transduction components, and are involved in various stimulatory or inhibitory signals [12][13][14][15][16]. The ERK is activated by various growth factors and phorbol esters, but are only weakly activated by inflammatory cytokines (tumor necrotic factor-α, interlleukin-1) and environmental stress.…”