CORE Metadata, citation and similar papers at core.ac.uk Provided by PubMed Central Clin Genet 2011: 80: 305–318 © 2011 John Wiley & Sons A/S Printed in Singapore. All rights reserved CLINICAL GENETICS doi: 10.1111/j.1399-0004.2011.01724.x Review Rab GTPases as regulators of endocytosis, targets of disease and therapeutic opportunities Agola JO, Jim PA, Ward HH, BasuRay S, Wandinger-Ness A. Rab JO Agolaa,b, PA Jima,b, GTPases as regulators of endocytosis, targets of disease and therapeutic HH Warda,b,SBasuRaya,b opportunities. and A Wandinger-Nessa,b © Clin Genet 2011: 80: 305–318. John Wiley & Sons A/S, 2011 aDepartment of Pathology and bCancer Rab GTPases are well-recognized targets in human disease, although are Center, University of New Mexico School of Medicine, Albuquerque, NM underexplored therapeutically. Elucidation of how mutant or dysregulated 87131, USA Rab GTPases and accessory proteins contribute to organ specific and systemic disease remains an area of intensive study and an essential foundation for effective drug targeting. Mutation of Rab GTPases or associated regulatory proteins causes numerous human genetic diseases. Cancer, neurodegeneration and diabetes represent examples of acquired human diseases resulting from the up- or downregulation or aberrant function of Rab GTPases. The broad range of physiologic processes and organ systems affected by altered Rab GTPase activity is based on pivotal roles in responding to cell signaling and metabolic demand through the coordinated regulation of membrane trafficking. The Rab-regulated processes of cargo sorting, cytoskeletal translocation of vesicles and appropriate fusion with the target membranes control cell metabolism, Key words: cancer – viability, growth and differentiation. In this review, we focus on Rab Charcot-Marie-Tooth disease – GTPase networks – mental retardation – GTPase roles in endocytosis to illustrate normal function and the neurodegenerative disease – consequences of dysregulation resulting in human disease. Selected neuropathies, pigmentation, immune examples are designed to illustrate how defects in Rab GTPase cascades and bleeding disorders alter endocytic trafficking that underlie neurologic, lipid storage, and metabolic bone disorders as well as cancer. Perspectives on potential Corresponding author: Dr Angela Wandinger-Ness, therapeutic modulation of GTPase activity through small molecule Department of Pathology interventions are provided. MSC 08 4640, University of New Conflict of interest Mexico HSC, Albuquerque, NM 87131, USA. There are no conflicts of interests to declare. Tel.: 505-272-1459; fax: 505-272-4193; Re-use of this article is permitted in accordance with the Terms and e-mail: [email protected] Conditions set out at http://wileyonlinelibrary.com/onlineopen#Online Received 9 March 2011, revised and Open_Terms accepted for publication 3 June 2011 The Ras superfamily of GTPases governs traf- normal function to the consequences of Rab ficking, cytoskeletal regulation and cell signal- GTPase or accessory protein dysfunction in genetic ing, through the interdigitated functions of Rab, or acquired diseases (Fig. 1, right side). Using Arf/Arl, Rho, Ras and Ran subfamily members. pathway specific examples we provide informa- In this review we focus on the Rab GTPases tion on the mechanistic underpinnings of normal that function in endocytosis and recycling, phago- function and alterations that lead to disease. Muta- cytosis, autophagy and pinocytosis (Fig. 1, left tions in the Rab GTPases and accessory proteins side). As noted in Fig. 1, endocytic Rab GTPases themselves, altered GTPase expression or activity also play vital roles in lysosome biogenesis and are relevant to neurologic and neurodegenerative ciliogenesis reviewed in Refs. (1–3). We contrast diseases, lipid storage disorders and cancer. The 305 Agola et al. Endocytic Rab GTPases Normal cellular and molecular functions Alterations in disease Endocytosis Degradation, Lysosome Ciliogenesis and Genetic Diseases Acquired Diseases and recycling autophagy, biogenesis and ciliary trafficking phagocytosis, regulated pinocytosis secretion Extracellular Lipid Specialized granule Development, Neurologic Pigmentation, Neuro- Cancer cargo uptake; homeostasis, formation and differentiation Diseases Bleeding, Immune, degenerative (e.g. Breast, integration of nutrient status, release for and signaling (e.g. Charcot-Marie- Skeletal/Bone, (e.g. Ovarian) signaling; vesicle metabolite and pigmentation, Tooth Disease Type Kidney Retinal Alzheimer’s trafficking, cargo receptor immune, bone and 2, Niemann-Pick Diseases and sorting, cyto- degradation, blood clotting Disease type C) (e.g. Griscelli Huntington’s skeletal pathogen functions Syndrome Type 2, diseases) translocation, clearance Choroideremia, membrane fusion Carpenter syndrome, Bardet- Biedl syndrome, arthrogryposis-renal- Metabolic Infectious cholestasis) (e.g. obesity, diabetes) Coordinated Rab GTPase function Integrated GTPase cascades Mutations in Rab GTPase or Altered GTPase on interconnected pathways (Rho, Arf/Arl, Rab, Ran, Ras) altered activity of GTPase or effector expression or activity Aberrant cell growth and differentiation Organ development and function Altered cell motility, adhesion, invasiveness Skeletal formation Increased lipid storage Normal cell differentiation and polarization Hypopigmentation, reduced coagulation, immune dysfunction Cell metabolism and homeostasis Kidney failure Immune function Osteopetrosis, craniosynostosis, polydactyly Coagulation Retinal and/or neuronal degeneration Fig. 1. Rab GTPases in normal cellular and molecular functions vs alterations in human disease. (Left panel) Normal functions of endocytic Rab GTPases in (i) endocytosis and recycling, (ii) degradative pathways (including autophagic and phagocytic pathways), (iii) lysosome biogenesis and regulated secretion, (iv) ciliogenesis and ciliary trafficking. (Right panel) Disease-causing alterations in Rab GTPase function may be acquired or genetic leading to loss of function, increased or decreased expression or activity. pivotal roles of small GTPases in disease make recycling circuits that utilize Rab17 and Rab25 them attractive targets for therapeutic intervention in addition to the ubiquitous Rab4, Rab5 and that have not yet been broadly explored. We also Rab11 GTPases (12). Early endosomes also regu- illustrate the fundamental aspects for GTPase reg- late return to the Golgi via Rab6 and the retromer ulation that provide possible paradigms for small complex, which may also interact with Rab7 (13, molecule therapeutics. 14). From late endosomes, return to the Golgi is regulated by Rab9, STX10 and Tip47 (15). Thus, endosomes and associated Rab GTPases serve in Rab GTPase regulated endocytosis, recycling cargo sorting for plasma membrane and Golgi and signaling recycling, as well as for degradation. Among the over 70 mammalian Rab GTPases (4), The early internalization and recycling circuits there are ∼20 Rab proteins with defined functions are subject to up- or downregulation in response to in endocytosis and related processes (Table 1). signaling and cellular demand. For example, epi- Early endocytic and recycling routes are summa- dermal growth factor receptor (EGFR) signaling rized in Fig. 2 (green section). Receptor-mediated through Ras increases the activity of Rin1 whose endocytosis occurs via clathrin-coated vesicles guanine nucleotide exchange factor (GEF) activity and is principally regulated by Rab5 and Rab21, causes Rab5 association with signal-transducing sharing common regulatory and effector pro- adaptor molecule 2 (STAM2) to increase EGFR teins (5, 6). Following internalization, sorting in internalization and degradation (16). Rab11a acti- the early endosome segregates molecules for vation on the other hand increases EGFR recy- return to the plasma membrane along fast (Rab4, cling in response to EGF signaling and the Rab14, Rab15) and slow (Rab11a, Rab15, Rab22a) Rab5 GTPase activating protein (GAP), RN-TRE, recycling routes (7–11). Epithelia have specialized decreases EGFR endocytosis through Grb2 (17). 306 Endocytosis and small molecules Table 1. Rab GTPase functions, networks and disease associationsa,b Rab Localization Rab function Pathological condition Endocytosis and recycling Rab4a Early endosomes and Regulates sorting and endocytic Upregulated in rodent model recycling endosomes recycling to the plasma of diabetic membrane cardiomyopathy, human systemic lupus erythematosus, Alzheimer’s disease and Down’s syndrome; inhibited in Niemann–Pick disease; downregulated in tumor cells Rab5a Plasma membrane, Endocytosis, early endosome Hyperactivated in lung clathrin-coated vesicles fusion, nuclear signaling adenocarcinoma; and early endosomes through APPL upregulated in Alzheimer’s Disease Rab9a Late endosomes Transport from endosome to Inhibited in Niemann–Pick C TGN; lipid transport; lysosome disease and lysosome-related organelle biogenesis Rab11a, Rab11b Golgi and recycling Trafficking from the TGN to Upregulated in Barrett’s (neuron specific) endosomes, early apical recycling endosomes epithelia; endosomes, and plasma membrane; neurodegeneration in phagosomes polarized trafficking in Huntington’s disease; epithelia; phagocytosis in Schwann cell macrophages demyelination in Charcot-Marie-Tooth type 4C disease; implicated in Batten disease Rab14 Early endosome, Golgi Endocytic recycling of transferrin; MHC class I cross-presentation; TGN to apical trafficking in epithelia; surfactant secretion in alveolar cells; insulin-dependent