REGULATION OF MITOGENESIS AND APOPTOSIS BY G PROTEINS

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Mitogen-activated protein kinase pathways, including the extracellular signal-regulated kinase (ERK) pathway and the c-Jun kinase (JNK) pathway, are activated by growth factors, cytokines, and G-protein coupled receptors. Based on amino acid sequence similarities, alpha12 and alpha13 belong to a distinct class of G protein alpha sub-units. The specific signaling pathways for this distance G protein class, including immediate effector molecules interacting directly with alpha12 and alpha13, remain unknown. My preliminary studies indicate that constitutively activated alpha12 and alpha13 induce mitogenesis of mammalian cells (NIH3T3) and Rat-1). In NIH3T3 and Rat-1 cells, alpha12 and alpha13 increase cellular growth rate and potentiate hormonal stimulation of the ERK pathway. In contrast, in COS-7 cells, alpha12 and alpha13 induce apoptosis and both alpha12 and alpha13 inhibit the ERK pathway in a Ras- and Raf-independent manner. This proposal focuses on the mechanisms that couple alpha12 and alpha13 to the regulation of the ERK and JNK pathways to understand functions of G12 and G13 and the effector pathways of alpha12 and alpha13 in the regulation of mitogenesis and apoptosis. Experiments will: i. characterize the effector molecules that interact directly with alpha12 and alpha13 and elucidate the molecular mechanisms by which alpha12 and alpha13 regulate ERK pathway; ii. Determine whether alpha 12 and alpha13 employ ERK or JNK pathways in the mitogenesis and which protein in each pathway is necessary and sufficient for mitogenesis; iii. Determine whether alpha12 and alpha13 employ ERK or JNK pathways in the apoptosis and which protein in each pathway is necessary and sufficient for apoptosis; iv. How Bcl-2 and Bax, two proteins that control programmed cell death, regulate apoptosis induced by alpha12 and alpha13; v. how sphingosine and sphingosine-1 phosphate (that regulate mitogenesis) and ceramide (that regulate apoptosis) regulate mitogenesis and apoptosis induced by alphas12 and alpha13.