GTPases in intracellular trafficking: An overview

doi:10.1016/j.semcdb.2010.12.004

Seminars in Cell & Developmental Biology

Volume 22, Issue 1, February 2011, Pages 1-2

https://doi.org/10.1016/j.semcdb.2010.12.004 Get rights and content

Abstract

Small GTPases that belong to the ras sub-families of Rab, Arf, and Rho, and the large GTPase dynamin, regulate intracellular trafficking. This issue of Seminars of Cell and Developmental Biology highlights topics regarding mechanisms by which these GTPases regulate the different steps of vesicular transport: vesicle formation, scission, targeting and fusion. In addition, the emerging roles of GTPases in coordination of individual transport steps as well as coordination of intracellular trafficking with other cellular processes are reviewed. Finally, common structures and mechanisms underlying the function of the ras-like GTPases and the importance of their function to human health and disease are discussed.

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Agonist-induced changes in RalA activities allows the prediction of the endocytosis of G protein-coupled receptors
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Citation Excerpt :
In order to study the roles of small G proteins on the intracellular trafficking of GPCRs, effects of small G proteins, such as Rab5, Rab23, ARF1, ARF6, and RalA were tested for the internalization of dopamine D2 receptor (D2R). These small G proteins are known to be involved in various processes such as vesicle formation, scission, targeting, and fusion formation [25,26]. Among these small G proteins, an active RalA mutant (GTP hydrolysis-resistant form, G23V) but not an inactive RalA mutant (GDP bound form, S28N) [8,9] inhibited the endocytosis of D2R in HEK-293 cells (Fig. 1A) and SH-SY5Y dopaminergic neuroblatoma cell lines (Fig. 1B), which are physiologically relevant cells for dopaminergic functions.
GTP binding proteins are classified into two families: heterotrimeric large G proteins which are composed of three subunits, and one subunit of small G proteins. Roles of small G proteins in the intracellular trafficking of G protein-coupled receptors (GPCRs) were studied. Among various small G proteins tested, GTP-bound form (G23V) of RalA inhibited the internalization of dopamine D₂ receptor independently of the previously reported downstream effectors of RalA, such as Ral-binding protein 1 and PLD. With high affinity for GRK2, active RalA inhibited the GPCR endocytosis by sequestering the GRK2 from receptors. When it was tested for several GPCRs including an endogenous GPCR, lysophosphatidic acid receptor 1, agonist-induced conversion of GTP-bound to GDP-bound RalA, which presumably releases the sequestered GRK2, was observed selectively with the GPCRs which have tendency to undergo endocytosis. Conversion of RalA from active to inactive state occurred by translocation of RGL, a guanine nucleotide exchange factor, from the plasma membrane to cytosol as a complex with Gβγ. These results suggest that agonist-induced Gβγ-mediated conversion of RalA from the GTP-bound form to the GDP-bound form could be a mechanism to facilitate agonist-induced internalization of GPCRs.
Characterization of enzymes from Legionella pneumophila involved in reversible adenylylation of Rab1 protein
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Citation Excerpt :
2′-(or-3′)-O-(N-methylanthraniloyl) guanosine 5′-triphosphate, trisodium salt. These regulatory proteins achieve a tight temporal and spatial control of Rab activation and inactivation in eukaryotes (4–7). Macrophages use vesicular trafficking pathways to ensure degradation of phagocytosed bacteria.
After the pathogenic bacterium Legionella pneumophila is phagocytosed, it injects more than 250 different proteins into the cytoplasm of host cells to evade lysosomal digestion and to replicate inside the host cell. Among these secreted proteins is the protein DrrA/SidM, which has been shown to modify Rab1b, a main regulator of vesicular trafficking in eukaryotic cells, by transfer of adenosine monophosphate (AMP) to Tyr⁷⁷. In addition, Legionella provides the protein SidD that hydrolytically reverses the covalent modification, suggesting a tight spatial and temporal control of Rab1 function by Legionella during infection. Small angle x-ray scattering experiments of DrrA allowed us to validate a tentative complex model built by combining available crystallographic data. We have established the effects of adenylylation on Rab1 interactions and properties in a quantitative way. In addition, we have characterized the kinetics of DrrA-catalyzed adenylylation as well as SidD-catalyzed deadenylylation toward Rab1 and have determined the nucleotide specificities of both enzymes. This study enhances our knowledge of proteins subverting Rab1 function at the Legionella-containing vacuole.
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Citation Excerpt :
Cortactin can also stabilize Arp2/3-mediated F-actin branching in vitro [11], and this activity may be critical for the stability of F-actin-rich cellular protrusions in vivo [12]. The SH3-domain of cortactin has been demonstrated to interact with a variety of proteins including: Arp2/3 stimulating N-WASP [13]; the WASP-interacting protein WIP [14]; the missing in metastasis protein, MIM [15]; the endocytic GTPase dynamin-2 [16]; the receptor endocytosis-regulator scaffold CD2AP [17]; the tight junction (TJ) protein ZO-1 [18]; the synaptic adaptor protein Shank2 [19]; the Cdc42 activator guanine nucleotide exchange factor (GEF) faciogenital dysplasia 1 (FGD1) [20]; as well as other important cellular modulating proteins. This suggests an important, central role for cortactin in a variety of biological processes related to cell proliferation, migration, invasion and endocytosis; all processes which require regulated actin polymerization [21–27].
Cortactin is an F-actin binding protein that functions as a scaffold to regulate Arp2/3 mediated actin polymerization in lamellipodia and invadopodia formation as well as functioning in cell migration and endocytosis of many different cell types. In light of the fact that regulated actin polymerization is critical for many cellular processes we launched a search for novel cortactin interactions with cellular proteins that might indicate heretofore undescribed biological activities supported by cortactin. Using a modified stable isotope labeling in cell culture (SILAC) approach in HEK293 cells and Flag-tagged cortactin (F-cortactin) as bait, we identified a limited set of cortactin interactions including several proteins which have not previously been identified as cortactin associated proteins. Among these were serine/threonine-protein phosphatase 2A subunit beta (PP2A-beta) and RCC2/TD60, a Rac guanine nucleotide exchange factor (GEF) required for completion of mitosis and cytokinesis. The interaction between cortactin and RCC2/TD60 was verified in cell lysates immunoprecitated with anti-RCC2/TD60 antibody. Furthermore, cortactin was localized by immunofluorescence in the equatorial plane of dividing HeLa cells in the region where RCC2/TD60 has previously been localized thus providing support for a complex containing cortactin and RCC2/TD60 complex that may play a functional role in cells undergoing mitosis.
Unveiling the Differences in Signaling and Regulatory Mechanisms between Dopamine D<inf>2</inf> and D<inf>3</inf> Receptors and Their Impact on Behavioral Sensitization
2023, International Journal of Molecular Sciences
RyR2/IRBIT regulates insulin gene transcript, insulin content, and secretion in the insulinoma cell line INS-1
2022, Scientific Reports
Capturing membrane trafficking events during 3D angiogenic development in vitro
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EditorialGTPases in intracellular trafficking: An overview

Abstract

Current Opinion in Cell Biology

Cell

The Journal of Biological Chemistry

Current Opinion in Cell Biology

Seminars in Cell & Developmental Biology

Seminars in Cell & Developmental Biology

Current Opinion in Cell Biology

Seminars in Cell & Developmental Biology

Seminars in Cell & Developmental Biology

Seminars in cell & developmental biology

Editorial
GTPases in intracellular trafficking: An overview