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.

The B cell antigen receptor complex is a hetero-oligomeric structure composed of antigen binding, membrane immunoglobulin, and transducer-transporter substructures. The transducer-transporter substructure is composed of disulfide-linked dimers of immunoglobulin (Ig)-alpha and Ig-beta/gamma subunits that are products of the mb-1(alpha) and B29 (beta/gamma) genes. Although the receptor complex associates with Src family kinases that are activated after receptor ligation, the site of interaction of these and other cytoplasmic effector molecules with receptor subunits is unknown. The cytoplasmic tails of Ig-alpha and Ig-beta chains were found to associate with distinct sets of effector molecules. The Ig-alpha chain cytoplasmic domain bound to the Src family kinases Lyn and Fyn, phosphatidylinositol-3 kinase (PI-3 kinase), and an unidentified 38-kilodalton phosphoprotein; the cytoplasmic tail of Ig-beta bound PI-3 kinase and unidentified 40- and 42-kilodalton phosphoproteins. Binding activity was found to occur within a 26-amino acid sequence of Ig-alpha and Ig-beta that contains a motif [(Asp or Glu)-(any amino acid)7-(Asp or Glu)-Tyr-(any amino acid)3-Leu-(any amino acid)7-Tyr-(any amino acid)2-(Leu or Ile)] previously implicated in signal transduction via other receptors including the Fc epsilon receptor I and the T cell antigen receptor. These findings indicate that the subunits act independently to activate distinct second messenger pathways.

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