Arrestin Regulation of Small GTPases
The regulation of small GTPases by arrestins is a relatively new way by which arrestin can exert influence over cell signalling cascades, hence, molecular interactions and specific binding partners are still being discovered. A pathway showcasing the regu
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Contents 1 What Are Small GTPases? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Arrestin Regulation of Small GTPases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Physiological Relevance of β-Arrestin and Small GTPase Interaction . . . . . . . . . . . . . . . . . . . 4 Therapeutic Targeting of β-Arrestin and Small GTPase Interaction . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract The regulation of small GTPases by arrestins is a relatively new way by which arrestin can exert influence over cell signalling cascades, hence, molecular interactions and specific binding partners are still being discovered. A pathway showcasing the regulation of GTPase activity by β-arrestin was first elucidated in 2001. Since this original study, growing evidence has emerged for arrestin modulation of GTPase activity through direct interactions and also via the scaffolding of GTPase regulatory proteins. Given the importance of small GTPases in a variety of essential cellular functions, pharmacological manipulation of this pathway may represent an area with therapeutic potential, particularly with respect to cancer pathology and cardiac hypertrophy. Keywords Small GTPase • Guanine nucleotide exchange factor (GEF) • GTPase-activating protein (GAP) • β-Arrestin • ARHGAP21
R.T. Cameron • G.S. Baillie (*) Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G128QQ, UK e-mail: [email protected] V.V. Gurevich (ed.), Arrestins - Pharmacology and Therapeutic Potential, Handbook of Experimental Pharmacology 219, DOI 10.1007/978-3-642-41199-1_19, © Springer-Verlag Berlin Heidelberg 2014
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R.T. Cameron and G.S. Baillie
1 What Are Small GTPases? Small GTPases are monomeric GTP-binding proteins with molecular weights ranging from 20 to 40 kDa. They cycle between biologically active GTP- and inactive GDP-bound conformations. The exchange of GDP for GTP is mediated by a guanine nucleotide exchange factor (GEF), which in turn promotes interaction with downstream effectors. The intrinsic GTPase activity of small GTPases is relatively slow and is enhanced through GTPase-activating proteins (GAPs). These regulators of GTPase activity either can be specific to individual GTPases or can have subfamily specificity (Takai et al. 2001). The structural properties of GTPases are highly conserved and serve as molecular switches, where exchange of GDP for GTP is a versatile way to alter affinities for various effector proteins to allow for the conversion of extracellular signals into a wide variety of cellular outcomes (Bourne et al. 1991). GTPases were first discovered in the 1980s as the oncogenes of rat sar
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