How does the G protein, G_i2, transduce mitogenic signals?

Abstract

Serpentine receptors coupled to the heterotrimeric G protein, Gi2, are capable of stimulating DNA synthesis in a variety of cell types. A common feature of the Gi2-coupled stimulation of DNA synthesis is the activation of the mitogen-activated protein kinases (MAPKs). The regulation of MAPK activation by the Gi2-coupled thrombin and acetylcholine muscarinic M2 receptors occurs by a sequential activation of a network of protein kinases. The MAPK kinase (MEK) which phosphorylates and activates MAPK is also activated by phosphorylation. MEK is phosphorylated and activated by either Raf or MEK kinase (MEKK). Thus, Raf and MEKK converge at MEK to regulate MAPK. Gi2-coupled receptors are capable of activating MEK and MAPK by Raf-dependent and Raf-independent mechanisms. Pertussis toxin catalyzed ADP-ribosylation of a12 inhibits both the Raf-dependent and-independent pathways activated by G12-coupled receptors. The Raf-dependent pathway involves Ras activation, while the Raf-independent activation of MEK and MAPK does not involve Ras. The Raf-independent activation of MEK and MAPK most likely involves the activation of MEKK. The vertebrate MEKK is homologous to the Stel 1 and Byr2 protein kinases in the yeast Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively. The yeast Stel 1 and Byr2 protein kinases are involved in signal transduction cascades initiated by pheromone receptors having a 7 membrane spanning serpentine structure coupled to G proteins. MEKK appears to be conserved in the regulation of G protein-coupled signal pathways in yeast and vertebrates. Raf represents a divergence in vertebrates from the yeast pheromone-responsive protein kinase system. Defining MEKK and Raf as a divergence in the MAPK regulatory network provides a mechanism for differential regulation of this system by G12-coupled receptors as well as other receptor systems, including the tyrosine kinases.

Inactivation of Raf-1 by a Protein-tyrosine Phosphatase Stimulated by GTP and Reconstituted by Gαi/o Subunits

“…The signaling mechanisms for MAP kinase activation by mammalian G-coupled receptors are complex (18); it appears that specific G ␣ subunits may promote, inhibit, or possibly be indifferent to activation of MAP kinase by G ␤␥ . Complexity is also indicated by reports that overexpression of GTPase-impaired G ␣i2 caused transformation and activation of MAP kinase in Rat-1 but not NIH 3T3 cells (19), and that overexpression of GTPase-impaired G ␣o transformed NIH 3T3 cells (20).…”

Suppression of Escherichia coli alkB mutants by Saccharomyces cerevisiae genes

“…It is interesting to note that another protein, STE6, involved in the S. cerevisiae pheromone signal transduction pathway was recently shown to be a functional homolog of the mammalian multidrug resistance protein (MDR, or P glycoprotein) because expression of the mouse MDR3 gene in S. cerevisiae ste6 mutants suppressed the sterile phenotype of these cells (27). However, the STE6 protein is thought to be the membrane protein mediating export of the a-factor mating pheromone (24), and the STE11 protein kinase is believed to act intracellularly to signal the induction of specific mating gene expression (18). It is therefore unlikely that STE11 alone could act to prevent the intracellular accumulation of an alkylating agent in S. cerevisiae, and in support of this we found that ste11 null mutants and STE11-overexpressing cells display the same alkylation sensitivity as wild-type cells (data not shown).…”

Kinases: positive and negative regulators of apoptosis

“…44,45,[62][63][64][65][66] Ras is capable of activating both Raf [67][68][69] and Mekk; 70 however, activation of the Erk pathway can also occur in the absence of Ras activation. 71 The pathways leading to Erk activation are reported to be triggered by receptor tyrosine kinases, 72,73 G-protein linked receptors, [74][75][76] PKC, 71,77,78 and calcium. 46,[79][80][81][82] Several lines of evidence suggest that the Erk pathway has an important role in modulating the survival of hematopoietic cells.…”