Department of Biochemistry and Molecular Biology and Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
* Author for correspondence (e-mail: scaplan{at}unmc.edu)
Accepted 6 June 2005
![]() |
Summary |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: Eps15 homology (EH) domain, Endocytosis, Recycling
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Although the precise mechanisms that control endocytic recycling are not fully understood, our knowledge of the molecular machinery regulating internalization is extensive. Interactions between clathrin, the AP-2 adaptor protein complex and the GTPase dynamin facilitate the `pinching off' of clathrin-coated pits from the plasma membrane and the generation of clathrin-coated vesicles (Sorkin, 2004). Also recruited by AP-2 to the site of clathrin-coated pits are proteins containing Eps15 homology (EH) domains, such as the epidermal growth factor receptor tyrosine kinase substrate Eps15 (Benmerah et al., 1995
). Eps15 plays a crucial role in internalization events (Benmerah et al., 1998
), and EH-domain-containing (EHD) proteins along with their interaction partners form a network involved in endocytic transport (reviewed in Polo et al., 2003
).
The EH domain was originally identified as a stretch of 100 residues repeated three times at the N-terminus of Eps15 (Fazioli et al., 1993
; Wong et al., 1995
). EH domains are highly conserved, generally exhibiting sequence similarity of 50-60% (Wong et al., 1995
). EHD proteins are expressed in single-celled organisms such as yeast, as well as multicellular organisms including nematodes, plants and mammals (reviewed in Miliaras and Wendland, 2004
; Santolini et al., 1999
).
NMR spectroscopy has thus far yielded closely related structures for EH domains (reviewed in Confalonieri and Di Fiore, 2002). Each EH domain contains two calcium-binding helix-loop-helix motifs known as EF-hands, which are linked by a short anti-parallel ß-sheet. However, not all EF-hands are capable of calcium binding, and they have been termed either `canonical' or `pseudo' EF-hands, depending on their ability to bind calcium (Strynadka and James, 1989
).
EH domains interact with other proteins. Probing of phage-display libraries (Paoluzi et al., 1998) and a human fibroblast expression library has identified peptides containing NPF (asparagine-proline-phenylalanine) motifs as major targets for EH-domain binding (Salcini et al., 1997
). Several studies have demonstrated that NPF residues enter a conserved hydrophobic pocket within the EH domain, which allows close contact between the asparagine residue of the tripeptide and a highly conserved tryptophan residue in the EH domain (de Beer et al., 1998
; de Beer et al., 2000
). Mutation of this conserved tryptophan residue dramatically impairs binding of EH domains to NPF motifs, and the mechanism of binding is thought to be conserved among most EH domains (de Beer et al., 1998
).
Over 50 eukaryotic EHD proteins have been identified (reviewed in Miliaras and Wendland, 2004; Polo et al., 2003
). Several of these proteins, including Eps15, the related Eps15R protein, intersectin 1 and intersectin 2 have multiple EH domains (see Fig. 1). As a general rule, most EH domains are present in the N-terminal region of the protein, and many EHD proteins have central coiled-coils, which are important for homo- and hetero-oligomerization. Other domains have been identified in various EHD proteins, including SH3 domains, pleckstrin homology (PH) domains, guanine nucleotide exchange factors for Rho, proline-rich regions and ubiquitin interaction motifs (reviewed in Polo et al., 2003
).
|
Another related function ascribed to EHD proteins is regulation of actin dynamics (Duncan et al., 2001; Hussain et al., 2001
; Tang et al., 1997
; Wendland et al., 1996
). Some EHD proteins (e.g. Reps1 and POB1) regulate actin microfilaments by interacting with GTPase-activating proteins (GAPs) for the Rho family GTPases Rac1 and CDC42 (Ikeda et al., 1998
; Yamaguchi et al., 1997
). This in turn can lead to actin assembly and the formation of membrane ruffles at the cell surface (through Rac1) and actin-rich filopodia (through CDC42) (Hall, 1998
). Other EHD proteins, such as intersectin 1, regulate actin assembly by serving as guanine nucleotide exchange factors (GEFs) for CDC42 (Hussain et al., 2001
) and binding to the Wiscott Aldrich Syndrome protein (WASp) (McGavin et al., 2001
). WASp activates the Arp2/3 complex and stimulates nucleation of new actin filaments in response to extracellular signals (Millard et al., 2004
).
EHD proteins also play various roles in signal transduction (Adams et al., 2000; Tong et al., 2000a
; Tong et al., 2000b
), which is not surprising considering that many contain known signaling modules, including SH3 and proline-rich domains. The intersectin SH3 domain regulates Ras activation and indirectly controls activation of MAP kinase (Tong et al., 2000a
). Data also indicate that some EHD proteins act in the nucleus regulating transcription (Doria et al., 1999
; Poupon et al., 2002
; Vecchi et al., 2001
). For example, both Eps15 and Eps15R are involved in nucleocytoplasmic shuttling of RNA and proteins via the Rev export pathway (Doria et al., 1999
; Poupon et al., 2002
), and this activity is independent of endocytic events (Vecchi et al., 2001
).
Mammalian cells possess four highly homologous EHD proteins in which the EH domain is at the C-terminus (Mintz et al., 1999; Pohl et al., 2000
) (Fig. 1). Of all known EHD proteins identified, few have C-terminal EH domains. S. cerevisae is a notable exception: two C-terminal EHD proteins have been identified (Irs4p and YJL085w). However, neither of these proteins shares significant sequence similarity with the mammalian C-terminal EHD proteins outside the EH domain. The few identifiable C-terminal EHD proteins in other species are orthologs of the human C-terminal EHD protein family. The EHD proteins have been addressed recently in several excellent reviews (Confalonieri and Di Fiore, 2002
; Miliaras and Wendland, 2004
; Polo et al., 2003
; Santolini et al., 1999
); however, there has been very little focus on the mammalian C-terminal EHD proteins and their functions. Here, we highlight the growing consensus for functions of these C-terminal EHD proteins in endocytic transport events and outline some recent advances.
![]() |
Structure and organization of mammalian C-terminal EHD proteins |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Domain architecture
Predictably, the four human C-terminal EHD paralogs have the same domain architecture (Fig. 1). Sequence analyses using programs such as the UniProt protein resource (http://www.ebi.uniprot.org/index.html) show that, in addition to the C-terminal EH domain, these proteins have a central region that has a high probability of coiled-coil formation and a nucleotide-binding region near the N-terminus (Fig. 1). Several studies have shown that EHD proteins form homo- and hetero-oligomers (Caplan et al., 2002; Galperin et al., 2002
; Lee et al., 2005
), and oligomerization appears to be mediated by the coiled-coil region (Lee et al., 2005
). Although these proteins do not contain a transmembrane domain, they associate with membranes. It is not known whether the membrane association occurs through a direct interaction with lipids, or whether it is mediated by lipid-binding proteins; however, this association depends upon the ability to bind nucleotides (Grant et al., 2001
; Caplan et al., 2002
; Lee et al., 2005
; Lin et al., 2001
).
Nucleotide-binding
All mammalian C-terminal EHD proteins contain a putative P-loop motif, an ATP/GTP-binding site found in Ras-family proteins, myosin heavy-chains and other kinases (Saraste et al., 1990). A recent study has demonstrated that ATP is the primary nucleotide that binds to and is hydrolyzed by EHD1 (Lee et al., 2005
), although it remains possible that in vivo EHD1 might also be capable of binding and/or hydrolyzing GTP.
The first study to demonstrate the functional significance of the predicted nucleotide-binding P-loop utilized an in vivo endocytic assay to show that growing oocytes possessing a glycine-to-arginine mutation within the conserved P-loop of the C. elegans Rme-1 protein (the ortholog of human EHD1) exhibit impaired uptake of the yolk protein (Grant et al., 2001). This probably resulted from impaired recycling of the yolk receptors in these mutants (Grant et al., 2001
). These findings were in agreement with previous studies showing that mutations in the homologous glycine residue of the Ras P-loop decrease GTPase activity and render the protein oncogenic (Seeburg et al., 1984
). The equivalent mutation (G65R) in hEHD1 causes the protein to lose its association with membranes (Caplan et al., 2002
; Lin et al., 2001
).
Support for EHD1 nucleotide-binding activity also came from FRAP studies in living cells (Caplan et al., 2002). EHD1 localizes to a striking array of tubular and vesicular membrane structures (Caplan et al., 2002
). Following photobleaching of the tubular membranes containing GFP-EHD1 in human cell lines, the fluorescence signal returns to these structures within several minutes. This suggests that this protein cycles on and off the membranes (Caplan et al., 2002
), which is a hallmark of many nucleotide-binding proteins.
![]() |
Functions of mammalian C-terminal EHD proteins |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
The mode of binding is probably similar to that described for the EH domain of other EHD proteins (de Beer et al., 1998): mutation of the conserved tryptophan of EHD1 described above (W485A) impairs its binding to rabenosyn 5 (Naslavsky et al., 2004
). Since this residue is conserved in all four mammalian C-terminal EHD proteins, it is probably crucial for interacting with all NPF-containing binding partners for these proteins.
It is noteworthy that there are instances in which C-terminal EHD proteins can bind to the same interaction partners as the other EHD proteins. The NPF-containing protein stonin 2 interacts with Eps15, Eps15R, intersectin 1 (Martina et al., 2001) and, at least in vitro, EHD1 and EHD3. Numb interacts with Eps15 (Salcini et al., 1997
), as well as with EHD4 (Smith et al., 2004
). However, whether other NPF-containing proteins bind promiscuously to C-terminal and other EHD proteins remains to be seen.
Roles for C-terminal EHD proteins in endocytic transport and recycling
Given the number of C-terminal-EHD-interacting proteins known to have roles in endocytosis, the regulation of endocytic events is probably a major function of these proteins (Fig. 3). EHD1 localizes to endocytic structures and binds to various components of the endocytic machinery, including the clathrin heavy-chain and AP-2 (Mintz et al., 1999). Furthermore, genetic screens in C. elegans identified Rme-1 as an important mediator of yolk receptor recycling, as previously mentioned (Grant et al., 2001
). Mammalian EHD1 was also found to regulate the distribution of the endocytic recycling compartment (ERC) and control exit of transferrin and its receptor from the ERC (Lin et al., 2001
). In addition to regulating clathrin-dependent transport, EHD1 controls the endocytic recycling and transport of receptors internalized through clathrin-independent pathways. For example, the recycling of major histocompatibility complex class I (MHC-I) proteins is regulated by EHD1 (Caplan et al., 2002
), and overexpression of EHD4 stimulates clathrin-independent macropinocytosis of the nerve growth factor receptor (TrkA) in PC12 rat adrenal pheochromocytoma cells (Shao et al., 2002
).
|
C-terminal EHD proteins regulate the recycling of a wide array of proteins. The recycled cargo includes transferrin receptors (Lin et al., 2001; Naslavsky et al., 2004
; and see also Fig. 4), MHC-I proteins (Caplan et al., 2002
), the cystic fibrosis transmembrane conductance regulator (Picciano et al., 2003
), the insulin-regulated GLUT4 glucose transporter (Guilherme et al., 2004b
), HIV Nef (Larsen et al., 2004
) and long-term potentiation AMPA-type glutamate receptors at post-synaptic membranes (Park et al., 2004a
). Overall, these studies indicate a key role for mammalian C-terminal EHD proteins in endocytic recycling.
|
EHD2 plays an endocytic role in adipocytes, where it serves to connect endocytic events at the plasma membrane with the actin cytoskeleton through its interaction with EH-binding protein 1 (EHBP1) (Guilherme et al., 2004a). EHBP1 is an actin-binding protein, and its overexpression or that of EHD2 causes extensive actin reorganization. Internalization of transferrin or its transport during the early steps of the endocytic pathway en route to the early endosome is impaired in cells overexpressing either wild-type EHD2 or an EHD2 mutant that lacks the EH domain, and cells in which EHD2 is knocked-down by RNAi (Guilherme et al., 2004a
). In agreement with a role for EHD proteins in internalization are studies showing that they interact with components of the internalization machinery. EHD2 binds to the µ1 and µ2 subunits of the AP-1 and AP-2 adaptor complexes (Park et al., 2004b
), and EHD1 interacts with clathrin and the
-adaptin subunit of AP-2 (Rotem-Yehudar et al., 2001
). Moreover, treatment with IGF-1 leads to the colocalization of EHD1 with IGF-1 receptors at the plasma membrane (Rotem-Yehudar et al., 2001
) and presumably the recruitment of AP-2. Interestingly, Eps15 also binds to the
-adaptin subunit of AP-2 (Benmerah et al., 1996
) and stimulation of epidermal growth factor receptors leads to recruitment of Eps15 and AP-2 to the these receptors (van Delft et al., 1997
). However, it remains unclear whether Eps15 and C-terminal EHD proteins carry out similar scaffolding tasks for different receptors, or whether they compete for binding to
-adaptin and NPF-containing proteins.
![]() |
Perspectives |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
EHD1 has been the most extensively studied C-terminal EHD protein. To determine the specific functions of the other mammalian paralogs, it will be important to generate specific antibodies for each of the EHD proteins. While this goal has been complicated by the high degree of sequence identity between the proteins, the first step in understanding their function and the significance of EHD oligomerization will be determining whether they are all simultaneously expressed in the same cell types. Once this has been achieved, RNAi technology should allow us begin to address the functional differences between members of this family.
Many questions concerning the mechanisms by which C-terminal EHD proteins control endocytic transport remain. Among these are the significance of homo- and hetero-oligomerization, nucleotide binding, and interactions with binding partners. One of the key issues is understanding the mode by which C-terminal EHD proteins coordinately regulate recycling with Rab proteins. As noted, Rab4 and Rab11 play crucial roles in endocytic recycling. C-terminal EHD proteins have been linked to Rab4-mediated transport via the EHD1rabenosyn-5 interaction (Naslavsky et al., 2004). However, thus far no attempts have been made to discover how C-terminal EHD proteins coordinate transport out of the ERC with Rab11 and its effectors. The identification of new interacting partners is likely to enhance our understanding of this complex mode of coordinate regulation.
![]() |
Acknowledgments |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Adams, A., Thorn, J. M., Yamabhai, M., Kay, B. K. and O'Bryan, J. P. (2000). Intersectin, an adaptor protein involved in clathrin-mediated endocytosis, activates mitogenic signaling pathways. J. Biol. Chem. 275, 27414-27420.
Benmerah, A., Gagnon, J., Begue, B., Megarbane, B., Dautry-Varsat, A. and Cerf-Bensussan, N. (1995). The tyrosine kinase substrate eps15 is constitutively associated with the plasma membrane adaptor AP-2. J. Cell Biol. 131, 1831-1838.[Abstract]
Benmerah, A., Begue, B., Dautry-Varsat, A. and Cerf-Bensussan, N. (1996). The ear of alpha-adaptin interacts with the COOH-terminal domain of the Eps 15 protein. J. Biol. Chem. 271, 12111-12116.
Benmerah, A., Lamaze, C., Begue, B., Schmid, S. L., Dautry-Varsat, A. and Cerf-Bensussan, N. (1998). AP-2/Eps15 interaction is required for receptor-mediated endocytosis. J. Cell Biol. 140, 1055-1062.
Caplan, S., Naslavsky, N., Hartnell, L. M., Lodge, R., Polishchuk, R. S., Donaldson, J. G. and Bonifacino, J. S. (2002). A tubular EHD1-containing compartment involved in the recycling of major histocompatibility complex class I molecules to the plasma membrane. EMBO J. 21, 2557-2567.
Carbone, R., Fre, S., Iannolo, G., Belleudi, F., Mancini, P., Pelicci, P. G., Torrisi, M. R. and Di Fiore, P. P. (1997). eps15 and eps15R are essential components of the endocytic pathway. Cancer Res. 57, 5498-5504.[Abstract]
Chen, H., Fre, S., Slepnev, V. I., Capua, M. R., Takei, K., Butler, M. H., Di Fiore, P. P. and De Camilli, P. (1998). Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis. Nature 394, 793-797.[CrossRef][Medline]
Confalonieri, S. and Di Fiore, P. P. (2002). The Eps15 homology (EH) domain. FEBS Lett. 513, 24-29.[CrossRef][Medline]
Conner, S. D. and Schmid, S. L. (2003). Regulated portals of entry into the cell. Nature 422, 37-44.[CrossRef][Medline]
de Beer, T., Carter, R. E., Lobel-Rice, K. E., Sorkin, A. and Overduin, M. (1998). Structure and Asn-Pro-Phe binding pocket of the Eps15 homology domain. Science 281, 1357-1360.
de Beer, T., Hoofnagle, A. N., Enmon, J. L., Bowers, R. C., Yamabhai, M., Kay, B. K. and Overduin, M. (2000). Molecular mechanism of NPF recognition by EH domains. Nat. Struct. Biol. 7, 1018-1022.[CrossRef][Medline]
de Renzis, S., Sonnichsen, B. and Zerial, M. (2002). Divalent Rab effectors regulate the sub-compartmental organization and sorting of early endosomes. Nat. Cell. Biol. 4, 124-133.[CrossRef][Medline]
Donaldson, J. G. (2003). Multiple roles for Arf6: sorting, structuring, and signaling at the plasma membrane. J. Biol. Chem. 278, 41573-41576.
Doria, M., Salcini, A. E., Colombo, E., Parslow, T. G., Pelicci, P. G. and Di Fiore, P. P. (1999). The eps15 homology (EH) domain-based interaction between eps15 and hrb connects the molecular machinery of endocytosis to that of nucleocytosolic transport. J. Cell Biol. 147, 1379-1384.
Duncan, M. C., Cope, M. J., Goode, B. L., Wendland, B. and Drubin, D. G. (2001). Yeast Eps15-like endocytic protein, Pan1p, activates the Arp2/3 complex. Nat. Cell Biol. 3, 687-690.[CrossRef][Medline]
Fazioli, F., Minichiello, L., Matoskova, B., Wong, W. T. and Di Fiore, P. P. (1993). eps15, a novel tyrosine kinase substrate, exhibits transforming activity. Mol. Cell. Biol. 13, 5814-5828.[Abstract]
Galperin, E., Benjamin, S., Rapaport, D., Rotem-Yehudar, R., Tolchinsky, S. and Horowitz, M. (2002). EHD3: a protein that resides in recycling tubular and vesicular membrane structures and interacts with EHD1. Traffic 3, 575-589.[CrossRef][Medline]
Grant, B., Zhang, Y., Paupard, M. C., Lin, S. X., Hall, D. H. and Hirsh, D. (2001). Evidence that RME-1, a conserved C. elegans EH-domain protein, functions in endocytic recycling. Nat. Cell Biol. 3, 573-579.[CrossRef][Medline]
Guilherme, A., Soriano, N. A., Bose, S., Holik, J., Bose, A., Pomerleau, D. P., Furcinitti, P., Leszyk, J., Corvera, S. and Czech, M. P. (2004a). EHD2 and the Novel EH Domain Binding Protein EHBP1 Couple Endocytosis to the Actin Cytoskeleton. J. Biol. Chem. 279, 10593-10605.
Guilherme, A., Soriano, N. A., Furcinitti, P. S. and Czech, M. P. (2004b). Role of EHD1 and EHBP1 in perinuclear sorting and insulin-regulated GLUT4 recycling in 3T3-L1 adipocytes. J. Biol. Chem. 279, 40062-40075.
Hales, C. M., Vaerman, J. P. and Goldenring, J. R. (2002). Rab11 family interacting protein 2 associates with Myosin Vb and regulates plasma membrane recycling. J. Biol. Chem. 277, 50415-50421.
Hall, A. (1998). Rho GTPases and the actin cytoskeleton. Science 279, 509-514.
Hussain, N. K., Jenna, S., Glogauer, M., Quinn, C. C., Wasiak, S., Guipponi, M., Antonarakis, S. E., Kay, B. K., Stossel, T. P., Lamarche-Vane, N. et al. (2001). Endocytic protein intersectin-l regulates actin assembly via Cdc42 and N-WASP. Nat. Cell Biol. 3, 927-932.[CrossRef][Medline]
Ikeda, M., Ishida, O., Hinoi, T., Kishida, S. and Kikuchi, A. (1998). Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral. J. Biol. Chem. 273, 814-821.
Kessels, M. M. and Qualmann, B. (2004). The syndapin protein family: linking membrane trafficking with the cytoskeleton. J. Cell Sci. 117, 3077-3086.
Larsen, J. E., Massol, R. H., Nieland, T. J. and Kirchhausen, T. (2004). HIV Nef-mediated major histocompatibility complex class I down-modulation is independent of Arf6 activity. Mol. Biol. Cell 15, 323-331.
Lee, D. W., Zhao, X., Scarselletta, S., Schweinsberg, P. J., Eisenberg, E., Grant, B. D. and Greene, L. E. (2005). ATP Binding regulates oligomerization and endosome association of RME-1 family proteins. J. Biol. Chem. 280, 17213-17220.
Lin, S. X., Grant, B., Hirsh, D. and Maxfield, F. R. (2001). Rme-1 regulates the distribution and function of the endocytic recycling compartment in mammalian cells. Nat. Cell Biol. 3, 567-572.[CrossRef][Medline]
Mammoto, A., Ohtsuka, T., Hotta, I., Sasaki, T. and Takai, Y. (1999). Rab11BP/Rabphilin-11, a downstream target of rab11 small G protein implicated in vesicle recycling. J. Biol. Chem. 274, 25517-25524.
Martina, J. A., Bonangelino, C. J., Aguilar, R. C. and Bonifacino, J. S. (2001). Stonin 2, an adaptor-like protein that interacts with components of the endocytic machinery. J. Cell Biol. 153, 1111-1120.
McGavin, M. K., Badour, K., Hardy, L. A., Kubiseski, T. J., Zhang, J. and Siminovitch, K. A. (2001). The intersectin 2 adaptor links Wiskott Aldrich Syndrome protein (WASp)-mediated actin polymerization to T cell antigen receptor endocytosis. J. Exp. Med. 194, 1777-1787.
Miliaras, N. B. and Wendland, B. (2004). EH Proteins: Multivalent Regulators of Endocytosis (and Other Pathways). Cell Biochem. Biophys. 41, 295-318.[CrossRef][Medline]
Millard, T. H., Sharp, S. J. and Machesky, L. M. (2004). Signalling to actin assembly via the WASP (Wiskott-Aldrich syndrome protein)-family proteins and the Arp2/3 complex. Biochem. J. 380, 1-17.[CrossRef][Medline]
Mintz, L., Galperin, E., Pasmanik-Chor, M., Tulzinsky, S., Bromberg, Y., Kozak, C. A., Joyner, A., Fein, A. and Horowitz, M. (1999). EHD1 an EH-domain-containing protein with a specific expression pattern. Genomics 59, 66-76.[CrossRef][Medline]
Naslavsky, N., Boehm, M., Backlund, P. S., Jr and Caplan, S. (2004). Rabenosyn-5 and EHD1 Interact and Sequentially Regulate Protein Recycling to the Plasma Membrane. Mol. Biol. Cell 15, 2410-2422.
Nielsen, E., Christoforidis, S., Uttenweiler-Joseph, S., Miaczynska, M., Dewitte, F., Wilm, M., Hoflack, B. and Zerial, M. (2000). Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain. J. Cell Biol. 151, 601-612.
Paoluzi, S., Castagnoli, L., Lauro, I., Salcini, A. E., Coda, L., Fre, S., Confalonieri, S., Pelicci, P. G., Di Fiore, P. P. and Cesareni, G. (1998). Recognition specificity of individual EH domains of mammals and yeast. EMBO J. 17, 6541-6550.
Park, M., Penick, E. C., Edwards, J. G., Kauer, J. A. and Ehlers, M. D. (2004a). Recycling endosomes supply AMPA receptors for LTP. Science 305, 1972-1975.
Park, S. Y., Ha, B. G., Choi, G. H., Ryu, J., Kim, B., Jung, C. Y. and Lee, W. (2004b). EHD2 interacts with the insulin-responsive glucose transporter (GLUT4) in rat adipocytes and may participate in insulin-induced GLUT4 recruitment. Biochemistry 43, 7552-7562.[CrossRef][Medline]
Picciano, J. A., Ameen, N., Grant, B. D. and Bradbury, N. A. (2003). Rme-1 regulates the recycling of the cystic fibrosis transmembrane conductance regulator. Am. J. Physiol. Cell Physiol. 285, C1009-C1018.
Pohl, U., Smith, J. S., Tachibana, I., Ueki, K., Lee, H. K., Ramaswamy, S., Wu, Q., Mohrenweiser, H. W., Jenkins, R. B. and Louis, D. N. (2000). EHD2, EHD3, and EHD4 encode novel members of a highly conserved family of EH domain-containing proteins. Genomics 63, 255-262.[CrossRef][Medline]
Polo, S., Confalonieri, S., Salcini, A. E. and Di Fiore, P. P. (2003). EH and UIM: endocytosis and more. Sci STKE 2003, re17.
Poupon, V., Polo, S., Vecchi, M., Martin, G., Dautry-Varsat, A., Cerf-Bensussan, N., Di Fiore, P. P. and Benmerah, A. (2002). Differential nucleocytoplasmic trafficking between the related endocytic proteins Eps15 and Eps15R. J. Biol. Chem. 277, 8941-8948.
Prekeris, R., Klumperman, J. and Scheller, R. H. (2000). A Rab11/Rip11 protein complex regulates apical membrane trafficking via recycling endosomes. Mol. Cell 6, 1437-1448.[CrossRef][Medline]
Ren, M., Xu, G., Zeng, J., De Lemos-Chiarandini, C., Adesnik, M. and Sabatini, D. D. (1998). Hydrolysis of GTP on rab11 is required for the direct delivery of transferrin from the pericentriolar recycling compartment to the cell surface but not from sorting endosomes. Proc. Natl. Acad. Sci. USA 95, 6187-6192.
Rotem-Yehudar, R., Galperin, E. and Horowitz, M. (2001). Association of insulin-like growth factor 1 receptor with EHD1 and SNAP29. J. Biol. Chem. 276, 33054-33060.
Salcini, A. E., Confalonieri, S., Doria, M., Santolini, E., Tassi, E., Minenkova, O., Cesareni, G., Pelicci, P. G. and Di Fiore, P. P. (1997). Binding specificity and in vivo targets of the EH domain, a novel protein-protein interaction module. Genes Dev. 11, 2239-2249.
Santolini, E., Salcini, A. E., Kay, B. K., Yamabhai, M. and Di Fiore, P. P. (1999). The EH network. Exp. Cell Res. 253, 186-209.[CrossRef][Medline]
Saraste, M., Sibbald, P. R. and Wittinghofer, A. (1990). The P-loop a common motif in ATP- and GTP-binding proteins. Trends Biochem. Sci. 15, 430-434.[CrossRef][Medline]
Seeburg, P. H., Colby, W. W., Capon, D. J., Goeddel, D. V. and Levinson, A. D. (1984). Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature 312, 71-75.[CrossRef][Medline]
Shao, Y., Akmentin, W., Toledo-Aral, J. J., Rosenbaum, J., Valdez, G., Cabot, J. B., Hilbush, B. S. and Halegoua, S. (2002). Pincher, a pinocytic chaperone for nerve growth factor/TrkA signaling endosomes. J. Cell Biol. 157, 679-691.
Smith, C. A., Dho, S. E., Donaldson, J., Tepass, U. and McGlade, C. J. (2004). The Cell Fate Determinant Numb Interacts with EHD/Rme-1 Family Proteins and Has a Role in Endocytic Recycling. Mol. Biol. Cell 15, 3698-708.
Sorkin, A. (2004). Cargo recognition during clathrin-mediated endocytosis: a team effort. Curr. Opin. Cell Biol. 16, 392-399.[CrossRef][Medline]
Strynadka, N. C. and James, M. N. (1989). Crystal structures of the helix-loop-helix calcium-binding proteins. Annu. Rev. Biochem. 58, 951-998.[CrossRef][Medline]
Tang, H. Y., Munn, A. and Cai, M. (1997). EH domain proteins Pan1p and End3p are components of a complex that plays a dual role in organization of the cortical actin cytoskeleton and endocytosis in Saccharomyces cerevisiae. Mol. Cell. Biol. 17, 4294-4304.[Abstract]
Tong, X. K., Hussain, N. K., Adams, A. G., O'Bryan, J. P. and McPherson, P. S. (2000a). Intersectin can regulate the Ras/MAP kinase pathway independent of its role in endocytosis. J. Biol. Chem. 275, 29894-29899.
Tong, X. K., Hussain, N. K., de Heuvel, E., Kurakin, A., Abi-Jaoude, E., Quinn, C. C., Olson, M. F., Marais, R., Baranes, D., Kay, B. K. et al. (2000b). The endocytic protein intersectin is a major binding partner for the Ras exchange factor mSos1 in rat brain. EMBO J. 19, 1263-1271.
Ullrich, O., Reinsch, S., Urbe, S., Zerial, M. and Parton, R. G. (1996). Rab11 regulates recycling through the pericentriolar recycling endosome. J. Cell Biol. 135, 913-924.[Abstract]
van Delft, S., Schumacher, C., Hage, W., Verkleij, A. J. and van Bergen en Henegouwen, P. M. (1997). Association and colocalization of Eps15 with adaptor protein-2 and clathrin. J. Cell Biol. 136, 811-821.
Vecchi, M., Polo, S., Poupon, V., van de Loo, J. W., Benmerah, A. and Di Fiore, P. P. (2001). Nucleocytoplasmic shuttling of endocytic proteins. J. Cell Biol. 153, 1511-1517.
Wendland, B., McCaffery, J. M., Xiao, Q. and Emr, S. D. (1996). A novel fluorescence-activated cell sorter-based screen for yeast endocytosis mutants identifies a yeast homologue of mammalian eps15. J. Cell Biol. 135, 1485-1500.[Abstract]
Wilson, G. M., Fielding, A. B., Simon, G. C., Yu, X., Andrews, P. D., Hames, R. S., Frey, A. M., Peden, A. A., Gould, G. W. and Prekeris, R. (2005). The FIP3-Rab11 protein complex regulates recycling endosome targeting to the cleavage furrow during late cytokinesis. Mol. Biol. Cell 16, 849-860.
Wong, W. T., Schumacher, C., Salcini, A. E., Romano, A., Castagnino, P., Pelicci, P. G. and Di Fiore, P. (1995). A protein-binding domain, EH, identified in the receptor tyrosine kinase substrate Eps15 and conserved in evolution. Proc. Natl. Acad. Sci. USA 92, 9530-9534.
Xu, Y., Shi, H., Wei, S., Wong, S. H. and Hong, W. (2004). Mutually exclusive interactions of EHD1 with GS32 and Syndapin II. Mol. Membr. Biol. 21, 269-277.[CrossRef][Medline]
Yamaguchi, A., Urano, T., Goi, T. and Feig, L. A. (1997). An Eps homology (EH) domain protein that binds to the Ral-GTPase target, RalBP1. J. Biol. Chem. 272, 31230-31234.