Role of EHD1 and EHBP1 in Perinuclear Sorting and Insulin-regulated GLUT4 Recycling in 3T3-L1 Adipocytes

Guilherme, Adı́lson; Soriano, Neil A.; Furcinitti, Paul S.; Czech, Michael P.

doi:10.1074/jbc.m401918200

Cited by 108 publications

(113 citation statements)

References 48 publications

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“…Munc18c associates with syntaxin4 and thereby may inhibit the binding of GLUT4 vesicles to syntaxin4 in the absence of insulin (14). EH domain-containing protein 2 has been found to associate with GLUT4 (42), and it participates in GLUT4 endocytosis (43). Annexin II appears to be involved in GLUT4 translocation in a way that is not yet defined (44).…”

Section: Resultsmentioning

confidence: 99%

Temporal Dynamics of Tyrosine Phosphorylation in Insulin Signaling

et al. 2006

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The insulin-signaling network regulates blood glucose levels, controls metabolism, and when dysregulated, may lead to the development of type 2 diabetes. Although the role of tyrosine phosphorylation in this network is clear, only a limited number of insulin-induced tyrosine phosphorylation sites have been identified. To address this issue and establish temporal response, we have, for the first time, carried out an extensive, quantitative, mass spectrometrybased analysis of tyrosine phosphorylation in response to insulin. The study was performed with 3T3-L1 adipocytes stimulated with insulin for 0, 5, 15, and 45 min. It has resulted in the identification and relative temporal quantification of 122 tyrosine phosphorylation sites on 89 proteins. Insulin treatment caused a change of at least 1.3-fold in tyrosine phosphorylation on 89 of these sites. Among the responsive sites, 20 were previously known to be tyrosine phosphorylated with insulin treatment, including sites on the insulin receptor and insulin receptor substrate-1. The remaining 69 responsive sites have not previously been shown to be altered by insulin treatment. They were on proteins with a wide variety of functions, including components of the trafficking machinery for the insulin-responsive glucose transporter GLUT4. These results show that insulin-elicited tyrosine phosphorylation is extensive and implicate a number of hitherto unrecognized proteins in insulin action. Diabetes 55:2171-2179, 2006 M etabolic control is primarily regulated by the insulin-signaling network. In healthy individuals, insulin stimulates glucose uptake from the bloodstream into adipose tissue and skeletal muscle while inhibiting glucose production in the liver. Dysregulation of this network associated with insulin resistance causes an increase in blood glucose and lipid levels, often initially associated with an increase in insulin levels and eventually culminating in type 2 diabetes (1). Understanding the signaling network activated by insulin stimulation is crucial for identifying the causes and effects of network dysregulation and insulin resistance.Insulin binds to the insulin receptor at the cell surface and activates its tyrosine kinase activity, leading to autophosphorylation and phosphorylation of several receptor substrates. Phosphorylation of selected tyrosine sites on receptor substrates is known to activate different pathways leading to increased glucose uptake, lipogenesis, and glycogen and protein synthesis, as well as to stimulation of cell growth (1,2). In addition to activation of these pathways by tyrosine phosphorylation, several mechanisms of downregulating the response to insulin stimulation have also been identified. For instance, serine phosphorylation on insulin receptor substrate (IRS)-1 induced by a variety of factors has been shown to interfere with the activating effects of tyrosine phosphorylation by decreasing binding to the insulin receptor or increasing degradation of IRS-1 (1,3,4). Ser/Thr phosphorylation of the insulin receptor has also bee...

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Section: Resultsmentioning

confidence: 99%

Temporal Dynamics of Tyrosine Phosphorylation in Insulin Signaling

et al. 2006

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“…EHD1/mRme-1 has been shown to form dimers or hetero-oligomers with the highly related protein EHD3 (14). In addition, EHD1/mRme-1 interacts through its EH domain with an actin-associated protein EHBP1 that, like EHD1/mRme-1 itself, is required for insulinstimulated translocation of the GLUT4 to the plasma membrane (13). Finally, EHD1/mRme-1 has been shown to interact through its EH domain with Rabenosyn-5, a Rab4/Rab5 effector that plays an important role in transport from early endosomes to recycling endosomes (23).…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence indicated that a defect in recycling of the C. elegans yolk receptor RME-2, a low density lipoprotein receptor homologue, is the primary defect resulting in defective yolk uptake in RME-1 mutant oocytes (10). Many subsequent studies have identified other membrane proteins in both clathrin-dependent and clathrinindependent uptake pathways that require RME-1 family proteins to recycle from endosomes to the plasma membrane (12,13,15). Thus, RME-1 is a general regulator of protein transport from recycling endosomes back to the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

“…Not only is RME-1 critical in the recycling of the transferrin receptor internalized by clathrin-coated pits, but it is also involved in the recycling of major histocompatibility complex class 1 internalized in a clathrin-independent process (12). RME-1 family members also function in the perinuclear sorting and insulin-regulated recycling of GLUT4 in cultured adipocytes (13). Thus, RME-1 family proteins regulate the intracellular transport of a diverse group of membrane proteins.…”

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confidence: 99%

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ATP Binding Regulates Oligomerization and Endosome Association of RME-1 Family Proteins

Lee

Zhao

Scarselletta

et al. 2005

Journal of Biological Chemistry

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Members of the RME-1/mRme-1/EHD1 protein family have recently been shown to function in the recycling of membrane proteins from recycling endosomes to the plasma membrane. RME-1 family proteins are normally found in close association with recycling endosomes and the vesicles and tubules emanating from these endosomes, consistent with the proposal that these proteins directly participate in endosomal transport. RME-1 family proteins contain a C-terminal EH (eps15 homology) domain thought to be involved in linking RME-1 to other endocytic proteins, a coiled-coil domain thought to be involved in homo-oligomerization and an N-terminal Ploop domain thought to mediate nucleotide binding. In the present study, we show that both Caenorhabditis elegans and mouse RME-1 proteins bind and hydrolyze ATP. No significant GTP binding or hydrolysis was detected. Mutation or deletion of the ATP-binding P-loop prevented RME-1 oligomerization and at the same time dissociated RME-1 from endosomes. In addition, ATP depletion caused RME-1 to lose its endosome association in the cell, resulting in cytosolic localization. Taken together, these results indicate that ATP binding is required for oligomerization of mRme-1/EHD1, which in turn is required for its association with endosomes.

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“…Emerging evidence has implicated all four C-terminal EHD proteins in the process of endocytosis (26). EHD1, the best characterized C-terminal EHD protein thus far, has a well documented role in controlling recycling from the endocytic recycling compartment to the plasma membrane, a function similar to that attributed to Rab11 (31,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Although no direct interaction has been demonstrated between EHD proteins and Rab proteins, recent studies have shown that EHD1 interacts directly with certain Rab effectors.…”

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confidence: 99%

EHD1 and Eps15 Interact with Phosphatidylinositols via Their Eps15 Homology Domains

Naslavsky

Rahajeng

Chenavas

et al. 2007

Journal of Biological Chemistry

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The C-terminal Eps15 homology domain-containing protein, EHD1, regulates the recycling of receptors from the endocytic recycling compartment to the plasma membrane. In cells, EHD1 localizes to tubular and spherical recycling endosomes. To date, the mode by which EHD1 associates with endosomal membranes remains unknown, and it has not been determined whether this interaction is direct or via interacting proteins. Here, we provide evidence demonstrating that EHD1 has the ability to bind directly and preferentially to an array of phospholipids, preferring phosphatidylinositols with a phosphate at position 3. Previous studies have demonstrated that EH domains coordinate calcium binding and interact with proteins containing the tripeptide asparagine-proline-phenylalanine (NPF). Using two-dimensional nuclear magnetic resonance analysis, we now describe a new function for the Eps15 homology (EH) domain of EHD1 and show that it is capable of directly binding phosphatidylinositol moieties. Moreover, we have expanded our studies to include the C-terminal EH domain of EHD4 and the second of the three N-terminal EH domains of Eps15 and demonstrated that phosphatidylinositol binding may be a more general property shared by certain other EH domains. Further studies identified a positively charged lysine residue (Lys-483) localized within the third helix of the EH domain, on the opposite face of the NPF-binding pocket, as being critical for the interaction with the phosphatidylinositols.The internalization of receptors is a critical process for eukaryotic cells. Receptors can be internalized from the plasma membrane by a variety of well described mechanisms, including via clathrin-coated pits, independently of clathrin, and through caveolae (1). Once internalized, the small vesicles containing the internalized cargo fuse with early endosomes (also known as sorting endosomes), and the receptors are then either sent to late endosomes and on to the lysosomal pathway for degradation or recycled back to the plasma membrane, where they may participate in additional rounds of internalization (2). Receptor recycling occurs either directly from the sorting endosomes in a process known as "fast recycling" or indirectly in a process termed "slow" or "regulated" recycling (3). Slow recycling has been better characterized and traverses a complex series of tubular and vesicular membrane structures that emerge from the microtubule-organizing center and is collectively known as the endocytic recycling compartment (3, 4). Despite advances in recent years, the process of recycling is not as well understood as internalization.Among the key regulatory proteins that control endocytic transport and recycling are the Rab family of GTP-binding proteins (5-7). Over 60 different mammalian Rab proteins have been identified thus far, and their highly regulated GTP binding and subsequent hydrolysis lead to recruitment of a wide array of effector proteins that are important for vesicular transport and fusion processes within the endocytic pathways. For exa...

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Role of EHD1 and EHBP1 in Perinuclear Sorting and Insulin-regulated GLUT4 Recycling in 3T3-L1 Adipocytes

Cited by 108 publications

References 48 publications

Temporal Dynamics of Tyrosine Phosphorylation in Insulin Signaling

Temporal Dynamics of Tyrosine Phosphorylation in Insulin Signaling

ATP Binding Regulates Oligomerization and Endosome Association of RME-1 Family Proteins

EHD1 and Eps15 Interact with Phosphatidylinositols via Their Eps15 Homology Domains

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