Heterotrimeric G proteins and apoptosis: intersecting signaling pathways leading to context dependent phenotypes

Abstract

Apoptosis, a programmed cell death mechanism, is a fundamental process during the normal development and somatic maintenance of all multicellular organisms and thus is highly conserved and tightly regulated through numerous signaling pathways. Apoptosis is of particular clinical importance as its dysregulation contributes significantly to numerous human diseases, primarily through changes in the expression and activation of key apoptotic regulators. Each of the four families of heterotrimeric G proteins (G(s), G(i/o), G(q/11) and G(12/13)) has been implicated in numerous cellular signaling processes, including proliferation, transformation, migration, differentiation, and apoptosis. Heterotrimeric G protein signaling is an important but not widely studied mechanism regulating apoptosis. G protein Signaling and Apoptosis broadly cover two large bodies of literature and share numerous signaling pathways. Examination of the intersection between these two areas is the focus of this review. Several studies have implicated signaling through each of the four heterotrimeric G protein families to regulate apoptosis within numerous disease contexts, but the mechanism(s) are not well defined. Each G protein family has been shown to stimulate and/or inhibit apoptosis in a context-dependent fashion through regulating numerous downstream effectors including the Bcl-2 family, NF-kappaB, PI3 Kinase, MAP Kinases, and small GTPases. These cell-type specific and G protein coupled receptor dependent effects have led to a complex body of literature of G protein regulation of apoptosis. Here, we review the literature and summarize apoptotic signaling through each of the four heterotrimeric G protein families (and the relevant G protein coupled receptors), and discuss limitations and future directions for research on regulating apoptosis through G protein coupled mechanisms. Continued investigation in this field is essential for the identification of important targets for pharmacological intervention in numerous diseases.

Fig. (1). Apoptosis Signaling Pathways

The Intrinsic pathway is triggered by various stresses including hypoxia/ischemia, growth factor deprivation, and cell damage. These stimuli cause a disruption in the ratio of pro-apoptotic (BAX, BAK) to anti-apoptotic (Bcl-2, Bcl-xL) Bcl-2 family proteins at the mitochondria. Relative increase in the levels of the pro-apoptotic proteins allows for their homodimerization, and subsequent Cytochrome C efflux into the cytoplasm activates Apaf-1. Apaf-1 triggers Caspase-9 aggregation and activation and the subsequent caspase cascade. The extrinsic pathway is triggered by ligand binding to the death receptors, which causes receptor trimerization and activation. Activated receptors recruit adapter proteins, such as FADD, leading ultimately to the activation of Caspase-8 and the subsequent caspase cascade. Both pathways converge on Caspase-3, leading to apoptosis.

Fig. (2). The G Protein Cycle

Heterotrimeric G proteins comprise three subunits, α, β, and γ, which associate in the inactive Gα-GDP bound state. The seven transmembrane domain G protein coupled receptor (GPCR), denoted by R, is activated by ligand binding, L. The activated receptor, denoted by R*, associates with Gα and catalyzes the dissociation of GDP. The subsequent binding of GTP causes Gα to dissociate from Gβγ, exposing interaction sites on Gα and Gβγ through which these proteins can activate downstream effectors and transduce signals. Subsequent hydrolysis of GTP to GDP by the intrinsic GTPase activity of Gα causes inactivation and reassociation of the Gαβγ complex.