Unravelling the missing links and new paradigms

In the world ofmonomeric G proteins, the identities and functional roles ofthe corresponding GTPase-activating proteins (GAPs) have been extensively investigated. A number of GAPs for monomeric G proteins actually serve as their immediately downstream effectors, and it is believed that the same principle applies to trimeric G proteins. Supporting evidences for this analogy are the interactions between Gaq/PLCP (Berstein et al. 1992) and Gat1/cGMP PDEy (Arshavsky and Bownd 1992). However, the GAP role of the G protein effectors could not fit perfectly into some of the fast signalling events involving G proteins, such as the regulation of the opening time of ion channels and the turnover of the photo-activation of rhodopsin-transducin signalling pathway. Recent identification of RGS (regulators of G protein signalling) proteins provides the missing link on the regulatory mechanisms of the GTPase activity of Ga (see De Vries et al. 2000). RGS proteins which appear to accelerate the GTP hydrolysis of Ga are covered in detail in Chapter 7. There are indications of specific regulatory roles of RGS proteins on individual GPCR signalling pathway, which may be dependent on a combination of cell type-specific expression, tissue distribution, intracellular localization, post-translational modifications, and other functional domains on the RGS. Based on a functional screen of the pheromone response pathway in yeast, a group of three diverse proteins known as the activators of G protein signalling (AGS1-3) have been identified and they activate trimeric G protein signalling pathways in the absence of a typical receptor (reviewed in Cismowski etal. 2001). AGS1 defines a distinct member ofRas-related proteins. AGS2 is identical to mouse Tctexl, a protein that exists as a light chain component of dynein with unknown signalling function. AGS3 possesses a novel functional motif termed G protein regulatory/GoLoco motifs and it can be found in a number of distinct proteins including RaplGAP, human mosaic protein LGN, Purkinje cell protein-2. Each AGS protein activates G protein signalling, they do so by different mechanisms within the context of the G protein activation/deactivation cycle. AGS proteins provide unexpected mechanisms for regulating trimeric G protein signalling pathways and additional surprises are bound to lie ahead of us.

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