A tubular EHD1-containing compartment involved in the recycling of major histocompatibility complex class I molecules to the plasma membrane

Caplan, Steve; Naslavsky, Naava; Hartnell, Lisa M.; Lodge, Robert; Polishchuk, Roman; Donaldson, Julie G.; Bonifacino, Juan S.

doi:10.1093/emboj/21.11.2557

Cited by 272 publications

(429 citation statements)

References 54 publications

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“…Thus, ARF6 acts upstream of RAB5 in mediating dextran internalization, at least under the conditions of ectopic expression used here. On expression of ARF6-Q67L, TBC1D3 was recruited to and accumulated on enlarged vesicles ( Figure 4D), which have been previously characterized as ARF6-positive endosomes (Caplan et al, 2002), suggesting that ARF6-dependent relocalization of TBC1D3 might be part of its mechanism of action. To confirm this, we investigated the colocalization of TBC1D3 with another marker of this compartment, phosphatidylinositol 4,5-bisphosphate (PIP2), which can be detected in living cells by the GFP-tagged PH domain of phospholipase C␦ (Katan and Allen, 1999).…”

Section: Tbc1d3 Mediates Macropinocytosis By Acting In a Pathway Thatmentioning

confidence: 62%

The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway

Frittoli

Palamidessi

Pizzigoni

et al. 2008

MBoC

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The generation of novel genes and proteins throughout evolution has been proposed to occur as a result of whole genome and gene duplications, exon shuffling, and retrotransposition events. The analysis of such genes might thus shed light into the functional complexity associated with highly evolved species. One such case is represented by TBC1D3, a primatespecific gene, harboring a TBC domain. Because TBC domains encode Rab-specific GAP activities, TBC-containing proteins are predicted to play a major role in endocytosis and intracellular traffic. Here, we show that the TBC1D3 gene originated late in evolution, likely through a duplication of the RNTRE locus, and underwent gene amplification during primate speciation. Despite possessing a TBC domain, TBC1D3 is apparently devoid of Rab-GAP activity. However, TBC1D3 regulates the optimal rate of epidermal growth factor-mediated macropinocytosis by participating in a novel pathway involving ARF6 and RAB5. In addition, TBC1D3 binds and colocalize to GGA3, an ARF6-effector, in an ARF6-dependent manner, and synergize with it in promoting macropinocytosis, suggesting that the two proteins act together in this process. Accordingly, GGA3 siRNA-mediated ablation impaired TBC1D3-induced macropinocytosis. We thus uncover a novel signaling pathway that appeared after primate speciation. Within this pathway, a TBC1D3:GGA3 complex contributes to optimal propagation of signals, ultimately facilitating the macropinocytic process. INTRODUCTIONGene duplication, exon shuffling, and retrotransposition events played crucial roles during vertebrate evolution (Long, 2001;McLysaght et al., 2002;Brosius, 2003). About 5% of the human genome is composed of duplicated segments that emerged during the past 35 million years of primate evolution, resulting in the generation of novel protein functions (Courseaux and Nahon, 2001;Taylor and Raes, 2004).One of the cellular processes, whose regulation has became more and more complex and tightly regulated during evolution is endocytosis. Endocytosis serves to maintain cellular and organismal homeostasis by mediating the uptake of fluids, solutes, and signaling molecules and their receptors. Multiple mechanisms of endocytosis operate within a single cell (Conner and Schmid, 2003). Among them, two major categories are phagocytosis and pinocytosis, which mediate the uptake of particles or of fluid, respectively (Conner and Schmid, 2003).Pinocytosis encompasses a variety of different membraneentry routes and is invariably characterized by the relatively small size (50 -150 nm) of the internalized particles. Large volumes of fluid are, instead, engulfed by extension, folding, and closure of plasma membranes (PM) through a process termed macropinocytosis (Swanson and Watts, 1995). Macropinocytosis displays many similarities to phagocytosis; the biochemical and cellular components of these endocytic mechanisms have been best characterized in hematopoietic cells, in processes such as phagocytosis by macrophages in response to Fc receptor stimulation, or ma...

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Section: Tbc1d3 Mediates Macropinocytosis By Acting In a Pathway Thatmentioning

confidence: 62%

The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway

Frittoli

Palamidessi

Pizzigoni

et al. 2008

MBoC

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“…These expression data suggest a functional significance of EHD2 expression in the context of GLUT4 trafficking. Consistent with this possibility, recent studies with EHD1 and its Caenorhabditis elegans homolog RME-1 suggest that these proteins are part of the molecular machinery responsible for recycling of receptors to the plasma membrane (32)(33)(34). Furthermore, connections between EHD1 and endocytosis of IGF-1 receptor in Chinese hamster ovary cells has been described (35).…”

Section: Identification Of Ehd2 In Membrane Fractions From 3t3-l1mentioning

confidence: 73%

EHD2 and the Novel EH Domain Binding Protein EHBP1 Couple Endocytosis to the Actin Cytoskeleton

Guilherme

Soriano

Bose

et al. 2004

Journal of Biological Chemistry

139

181

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Here we identified two novel proteins denoted EH domain protein 2 (EHD2) and EHD2-binding protein 1 (EHBP1) that link clathrin-mediated endocytosis to the actin cytoskeleton. EHD2 contains an N-terminal P-loop and a C-terminal EH domain that interacts with NPF repeats in EHBP1. Disruption of EHD2 or EHBP1 function by small interfering RNA-mediated gene silencing inhibits endocytosis of transferrin into EEA1-positive endosomes as well as GLUT4 endocytosis into cultured adipocytes. EHD2 localizes with cortical actin filaments, whereas EHBP1 contains a putative actin-binding calponin homology domain. High expression of EHD2 or EHBP1 in intact cells mediates extensive actin reorganization. Thus EHD2 appears to connect endocytosis to the actin cytoskeleton through interactions of its N-terminal domain with membranes and its C-terminal EH domain with the novel EHBP1 protein.

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“…First, EHD proteins play a role in recycling from the endosome to the plasma membrane (20,21,25), and thus may be implicated in membrane shuttling from tubulovesicles to the plasma membrane of canaliculi. Second, purified EHD proteins can deform lipid bilayers both in vitro (19) and in vivo (26,27) to generate EHD-coated tubules that are in the same size range as tubulovesicles of gastric parietal cells (27,28). Third, they contain an EH domain homologous to the EH domain of the epsin interactor Eps15 (i.e., a domain predicting a potential interaction with the NPF motifs present in the C-terminal region of the epsins) (25, 29, 30).…”

Section: Resultsmentioning

confidence: 99%

Selective high-level expression of epsin 3 in gastric parietal cells, where it is localized at endocytic sites of apical canaliculi

Paradise

Chen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Epsin is a ubiquitin-binding endocytic adaptor, which is highly concentrated at clathrin-coated pits and coordinates acquisition of bilayer curvature with coat recruitment and cargo selection. Epsin is encoded by three distinct genes in mammals. Epsin 1 and 2 have broad tissue distribution with high-level expression in the brain. In contrast, epsin 3 was reported to be expressed primarily in immature keratinocytes. Here, we show that epsin 3 is selectively expressed at high levels in the stomach (including the majority of gastric cancers), where it is concentrated in parietal cells. In these cells, epsin 3 is enriched and colocalized with clathrin around apical canaliculi, the sites that control acidification of the stomach lumen via the exo-endocytosis of vesicles containing the H/K ATPase. Deletion of the epsin 3 gene in mice did not result in obvious pathological phenotypes in either the stomach or other organs, possibly because of overlapping functions of the other two epsins. However, levels of EHD1 and EHD2, two membrane tubulating proteins with a role in endocytic recycling, were elevated in epsin 3 knockout stomachs, pointing to a functional interplay of epsin 3 with EHD proteins in the endocytic pathway of parietal cells. We suggest that epsin 3 cooperates with other bilayer binding proteins with curvature sensing/generating properties in the specialized traffic and membrane remodeling processes typical of gastric parietal cells.adaptor protein | gastric cancer | Hip1R | EH domain | ezrin

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A tubular EHD1-containing compartment involved in the recycling of major histocompatibility complex class I molecules to the plasma membrane

Cited by 272 publications

References 54 publications

The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway

The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway

EHD2 and the Novel EH Domain Binding Protein EHBP1 Couple Endocytosis to the Actin Cytoskeleton

Selective high-level expression of epsin 3 in gastric parietal cells, where it is localized at endocytic sites of apical canaliculi

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