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

Guilherme, Adı́lson; Soriano, Neil A.; Bose, Sahana; Holik, John; Bose, Avirup; Pomerleau, Darcy P.; Furcinitti, Paul S.; Leszyk, John D.; Corvera, Silvia; Czech, Michael P.

doi:10.1074/jbc.m307702200

Cited by 141 publications

(194 citation statements)

References 53 publications

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“…Transfection of wild type EHD2 did not disturb myoblast fusion. Consistent with normal myoblast fusion, wild type EHD2 and myoferlin were colocalized at sites on the membrane and throughout the cytosol in a pattern consistent with previous reports describing a role for EHD2 in coupling endocytosis to actin cytoskeletal dynamics (28).…”

Section: Delayed Endocytic Recycling In Myoferlin Nullsupporting

confidence: 89%

“…It has previously been observed that EHD2 and its binding partner EHD2-binding protein 1 (EHBP1), localize to adjacent structures in regions of endocytosis and actin dynamics such as ruffled membranes and only colocalize in regions where the adjacent structures overlap (28). It is possible that myoferlin and EHBP1 compete for binding on EHD2 (Fig.…”

Section: Discussionmentioning

confidence: 99%

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The Endocytic Recycling Protein EHD2 Interacts with Myoferlin to Regulate Myoblast Fusion

Doherty

Demonbreun

Wallace

et al. 2008

Journal of Biological Chemistry

105

137

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Skeletal muscle is a multinucleated syncytium that develops and is maintained by the fusion of myoblasts to the syncytium. Myoblast fusion involves the regulated coalescence of two apposed membranes. Myoferlin is a membrane-anchored, multiple C2 domain-containing protein that is highly expressed in fusing myoblasts and required for efficient myoblast fusion to myotubes. We found that myoferlin binds directly to the eps15 homology domain protein, EHD2. Members of the EHD family have been previously implicated in endocytosis as well as endocytic recycling, a process where membrane proteins internalized by endocytosis are returned to the plasma membrane. EHD2 binds directly to the second C2 domain of myoferlin, and EHD2 is reduced in myoferlin null myoblasts. In contrast to normal myoblasts, myoferlin null myoblasts accumulate labeled transferrin and have delayed recycling. Introduction of dominant negative EHD2 into myoblasts leads to the sequestration of myoferlin and inhibition of myoblast fusion. The interaction of myoferlin with EHD2 identifies molecular overlap between the endocytic recycling pathway and the machinery that regulates myoblast membrane fusion.

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Section: Delayed Endocytic Recycling In Myoferlin Nullsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

The Endocytic Recycling Protein EHD2 Interacts with Myoferlin to Regulate Myoblast Fusion

Doherty

Demonbreun

Wallace

et al. 2008

Journal of Biological Chemistry

105

137

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“…1 A). Two immunoreactive species were observed of apparent sizes of 68 kDa (major) and 65 kDa (minor), corresponding to the sizes of Pincher (Shao et al, 2002) and the highly homologous Pincher family members, rEHD1/2 (Mintz et al, 1999;Guilherme et al, 2004), respectively. The 68 kDa protein was positively identified as Pincher in SCG neurons overexpressing an HA-tagged Pincher cDNA ( Fig.…”

Section: Pincher Mediates Trka Internalization and Endosomal Erk5 Sigmentioning

confidence: 99%

Pincher-Mediated Macroendocytosis Underlies Retrograde Signaling by Neurotrophin Receptors

Valdez¹,

Akmentin²,

Philippidou³

et al. 2005

J. Neurosci.

131

145

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Retrograde signaling by neurotrophins is crucial for regulating neuronal phenotype and survival. The mechanism responsible for retrograde signaling has been elusive, because the molecular entities that propagate Trk receptor tyrosine kinase signals from the nerve terminal to the soma have not been defined. Here, we show that the membrane trafficking protein Pincher defines the primary pathway responsible for neurotrophin retrograde signaling in neurons. By both immunofluorescence confocal and immunoelectron microscopy, we find that Pincher mediates the formation of newly identified clathrin-independent macroendosomes for Trk receptors in soma, axons, and dendrites. Trk macroendosomes are derived from plasma membrane ruffles and subsequently processed to multivesicular bodies. Pincher similarly mediates macroendocytosis for NGF (TrkA) and BDNF (TrkB) in both peripheral (sympathetic) and central (hippocampal) neurons. A unique feature of Pincher-Trk endosomes is refractoriness to lysosomal degradation, which ensures persistent signaling through a critical effector of retrograde survival signaling, Erk5 (extracellular signal-regulated kinase 5). Using sympathetic neurons grown in chamber cultures, we find that block of Pincher function, which prevents Trk macroendosome formation, eliminates retrogradely signaled neuronal survival. Pincher is the first distinguishing molecular component of a novel mechanistic pathway for endosomal signaling in neurons.

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“…Vertebrate EHDs show a distinct tissue expression pattern [7,8,[11][12][13] and intracellular localization. EHD1 was localized mainly to the endocytic recycling compartment (ERC) [7] with some localization on the plasma membrane and early endosomes [14,15], while EHD2 was localized to the plasma membrane [16,17]. EHD3 was located on early endosomes and the perinuclear tubular and vesicular structures of the recycling compartment [12,18] and EHD4 was localized to the plasma membrane, to vesicular structures [19] and to early endosomes [20].…”

Section: Introductionmentioning

confidence: 99%

EHDS are serine phosphoproteins: EHD1 phosphorylation is enhanced by serum stimulation

Fichtman

Ravid

Rapaport

et al. 2008

Cellular and Molecular Biology Letters

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Abbreviations used: AP-2 -adaptor protein complex-2; BSA -bovine serum albumin; CHOChinese hamster ovary; cpm -counts per minute; dFCS -dialyzed FCS; DMEM -Dulbecco modified eagle medium; EHBP1-EH domain binding protein 1; FCS -fetal calf serum; FYVE -phenylalanine-tyrosine-valine-glutamate; IGF-1R -insulin-like growth factor-1 receptor; mDHFR -mouse dihydrofolate reductase; MEM-Alpha -minimal essential medium-alpha; ORF -open reading frame; PBS -phosphate buffered saline; PKC -protein kinase C; PVDFpolyvinidilen difluoride; TLC -thin-layer chromatography; TLE -thin-layer electrophoresis Abstract: Endocytic processes are mediated by multiple protein-protein interacting modules and regulated by phosphorylation and dephosphorylation. The Eps15 homology domain containing protein 1 (EHD1) has been implicated in regulating recycling of proteins, internalized both in clathrin-dependent and clathrin-independent endocytic pathways, from the recycling compartment to the plasma membrane. EHD1 was found in a complex with clathrin, adaptor protein complex-2 (AP-2) and insulin-like growth factor-1 receptor (IGF-1R), and was shown to interact with Rabenosyn-5, SNAP29, EHBP1 (EH domain binding protein 1) and syndapin I and II. In this study, we show that EHD1, like the other human EHDs, undergoes serine-phosphorylation. Our results also indicate that EHD1 is a serum-inducible serine-phosphoprotein and that PKC (protein kinase C) is one of its kinases. In addition, we show that inhibitors of clathrin-mediated endocytosis decrease EHD1 phosphorylation, while inhibitors of caveolinmediated endocytosis do not affect EHD1 phosphorylation. The results of experiments in which inhibitors of endocytosis were employed strongly suggest that EHD1 phosphorylation occurs between early endosomes and the endocytic recycling compartment.

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

Cited by 141 publications

References 53 publications

The Endocytic Recycling Protein EHD2 Interacts with Myoferlin to Regulate Myoblast Fusion

The Endocytic Recycling Protein EHD2 Interacts with Myoferlin to Regulate Myoblast Fusion

Pincher-Mediated Macroendocytosis Underlies Retrograde Signaling by Neurotrophin Receptors

EHDS are serine phosphoproteins: EHD1 phosphorylation is enhanced by serum stimulation

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