Coated pits contain a resident membrane molecule(s) that binds clathrin AP-2 with high affinity. AP-2 binding to this site is likely to be the first step in coated pit assembly because this subunit functions as a template for the polymerization of clathrin into flat polygonal lattices. Integral membrane proteins involved in receptor mediated endocytosis cluster in the newly assembled pits as they invaginate and bud from the membrane. The AP-2 subunit is a multi-domain, molecular complex that can be separated by proteolysis into a brick-shaped core and ear-like appendage domains. This property has been used to identify the domain involved in the various stages of coated pit assembly and budding. The core of AP-2 is the domain that binds both to membranes and to triskelions during assembly. Triskelions are perfectly capable of forming lattices on the membrane bound cores. Clathrin lattices bound only to core domains were also able to invaginate normally. Limited proteolysis is also useful for further characterizing the AP-2 binding site. Elastase treatment of the inside membrane surface releases a peptide fraction that is able to bind AP-2 in solution and prevent it from interacting with membranes. Affinity purification of binding activity yielded a collection of peptides that was dominated by a 45-kD species. This is the candidate peptide for containing the AP-2-binding site. Therefore, the appendage domain does not directly participate in any of the assembly or invagination events required for coated pit function (Peeler, 1993).
The alpha subunit of the endocytotic AP2 adaptor complex contains a 30 kDa 'appendage' domain, which is joined to the rest of the protein via a flexible linker. The 1.9 Å resolution crystal structure of this domain reveals a single binding site for its ligands, which include amphiphysin, Eps15, and epsin. This domain when overexpressed in COS7 fibroblasts is shown to inhibit transferrin uptake, whereas mutants in which interactions with its binding partners are abolished do not. DPF/W motifs present in appendage domain-binding partners are shown to play a crucial role in their interactions with the domain. A single site for binding multiple ligands would allow for temporal and spatial regulation in the recruitment of components of the endocytic machinery (Owen, 1999).
The epidermal growth factor (EGF) receptor interacts with plasma membrane-associated adapter proteins during endocytosis through coated pits. Almost 50 percent of the total pool of alpha-adaptins is coimmunoprecipitated with the EGF receptor when A-431 cells are treated with EGF at 37 o C, but not at 4 o C. Partial proteolysis of alpha-adaptin suggesta that the amino-terminal domain is the region that associates with the EGF receptor. The extent of receptor-adaptin association increases in cells depleted of potassium to block endocytosis. These data suggest that receptor-adaptin association occurs in intact cells before coated pits are fully assembled (Sorkin, 1993).
The neu proto-oncogene product, p185neu (HER2, c-ErbB-2), encodes a cell-surface tyrosine kinase receptor with high oncogenic potential; this oncogenic potenetial correlates with increased tyrosine kinase activity and a rapid receptor internalization rate. To investigate the interactions and signal(s) leading to the endocytosis of Neu receptors, lateral mobility and internalization studies were employed. Fluorescence photobleaching recovery measurements revealed that activation of Neu receptors (induced by mutation or by agonistic antibodies) markedly reduces mobile fractions of these receptors. To elucidate the signals involved, other mutants, all carrying a constitutively dimerizing oncogenic mutation, were analyzed. A kinase-negative mutant and a mutant lacking all cytoplasmic tyrosine phosphorylation consensus sequences exhibits high mobile fractions, similar to nonactivated Neu. Retention of a single tyrosine autophosphorylation site (Tyr-1253) out of the five known such sites is sufficient to immobilize a large fraction of the receptor. For all mutants, internalization correlates with receptor immobilization and is blocked by treatments that interfere with coated pit structure, indicating that the immobilization is due to interactions with coated pits. This was supported by the coimmunoprecipitation of alpha-adaptin with only the constitutively activated Neu mutants. It is concluded that activated Neu receptors become stably associated with coated pits via plasma membrane adaptor complexes (AP-2). Efficient Neu receptor endocytosis requires activation, a functional kinase domain, and at least one tyrosine autophosphorylation site (Gilboa, 1995).
Neural cell adhesion molecule (NCAM) constitutes a group of cell surface glycoproteins that regulate cell-cell interactions in the developing and adult brain. Endocytosis is a mechanism which dynamically controls the amount of cell surface NCAM expression and may involve the rapid changes occurring in NCAM expression under certain physiological or pathological conditions. However, the endocytic pathway of NCAM has remained unknown. Using astrocytes in culture and immunofluorescence it has been show that NCAM is internalized and that the immunolabelling presents a high degree of colocalization with clathrin, alpha-adaptin and transferrin, suggesting that NCAM is endocytosed by a clathrin-dependent pathway. Potassium depletion which disrupts clathrin-mediated endocytosis, inhibits internalization of NCAM. Electron microscopy and immunogold studies also demonstrate that the surface of clathrin-coated vesicles are also immunolabelled for both alpha-adaptin and PSA-NCAM, the highly sialylated isoform of NCAM. Furthermore, immunoprecipation studies demonstrate that NCAM is associated with both clathrin and alpha-adaptin, a component of adaptor complex AP-2, in brain, neurons and astrocytes. These findings indicate that NCAM is mainly endocytosed via clathrin-coated vesicles, suggesting a possible mechanism that may contribute to the rapid changes in NCAM expression at the cell surface (Minana, 2001).
The ubiquitous eps15 protein was initially described as a substrate of the EGF receptor kinase. Its functions are not yet delineated and this work provides evidence for its possible role in endocytosis. A novel anti-eps15 antibody, 6G4, coimmunoprecipitates proteins of molecular mass 102 kD. In human cells, these proteins were identified as the alpha- and beta-adaptins of the AP-2 complex on the basis of their NH2- terminal sequence and their immunoreactivity with anti-alpha- and anti- beta-adaptin antibodies but not with anti-gamma-adaptin antibody. In addition, the anti-eps15 antibody coimmunoprecipitates metabolically labeled polypeptides with molecular mass of 50 and 17 kD, comparable to those of the two other components of the AP-2 complex, mu2 (not to be confused with the female-specific mutator Mu2 in Drosophila) and sigma 2. Constitutive association of eps15 with AP-2 was confirmed by two sets of experiments. First, eps15 was detected in immunoprecipitates of anti- alpha- and anti-beta-adaptin antibodies. Second, alpha- and beta- but not gamma-adaptins were precipitated by a glutathione-S-transferase eps15 fusion protein. The association of eps15 with AP-2 is ubiquitous and conserved between species, since it is observed in human lymphocytes and epithelial cells and in murine NIH3T3 fibroblasts. These results are in keeping with a recent study showing homology between the NH2-terminal domains of eps15 and the product of the gene END3, involved in clathrin-mediated endocytosis of the pheromone alpha factor in Saccharomyces cerevisiae, and suggest a possible role for eps15 in clathrin-mediated endocytosis in mammals (Benmerah, 1995).
The role of Eps15 in clathrin-mediated endocytosis is supported by two observations. First, it interacts specifically and constitutively with the plasma membrane adaptor AP-2. Second, its NH2 terminus shows significant homology to the NH2 terminus of yeast End3p, necessary for endocytosis of alpha-factor. To gain further insight into the role of Eps15-AP-2 association, their sites of interactions has been demonstrated. AP-2 binds to a domain of 72 amino acids (767-739) present in the COOH terminus of Eps15. This domain contains 4 of the 15 DPF repeats characteristic of the COOH-terminal domain of Eps15 and shares no homology with known proteins, including the related Epsl5r protein. Precipitation of proteolytic fragments of AP-2 with Eps15-derived fusion proteins containing the binding site for AP-2 showed that Eps15 binds specifically to a 40-kDa fragment corresponding to the ear of alpha-adaptin, a result confirmed by precipitation of Eps15 by alpha-adaptin-derived fusion proteins. These data indicate that this specific part of AP-2 binds to a cellular component and provide the tools for investigating the functions of the association between AP-2 and Eps15 (Benmerah, 1996).
Eps15 is a substrate of the EGF receptor tyrosine kinase. Activation of the EGF receptor by either EGF or TGF-alpha results in phosphorylation of Eps15. Stimulation of cells with PDGF or insulin does not lead to Eps15 phosphorylation, suggesting that phosphorylation of Eps15 is a receptor-specific process. Eps15 is constitutively associated with both alpha-adaptin and clathrin. Upon EGF stimulation, Eps15 and alpha-adaptin are recruited to the EGF receptor. Using a truncated EGF receptor mutant, it has been demonstrated that the regulatory domain of the cytoplasmic tail of the EGF receptor is essential for the binding of Eps15. Fractionation studies reveal that Eps15 is present in cell fractions enriched for plasma membrane and endosomal membranes. Immunofluorescence studies show that Eps15 colocalizes with adaptor protein-2 (AP-2) and partially with clathrin. No colocalization of Eps15 was observed with the early endosomal markers rab4 and rab5. These observations indicate that Eps15 is present in coated pits and coated vesicles of the clathrin-mediated endocytic pathway, but not in early endosomes. Neither AP-2 nor clathrin are required for the binding of Eps15 to coated pits or coated vesicles, since in membranes lacking AP-2 and clathrin, Eps15 still shows the same staining pattern. These findings suggest that Eps15 may play a critical role in the recruitment of active EGF receptors into coated pit regions before endocytosis of ligand-occupied EGF receptors (van Delft, 1997).
Recent data have shown that Eps15, a newly identified component of clathrin-coated pits constitutively associates with the AP-2 complex, is required for receptor-mediated endocytosis. However, its precise function remains unknown. Interestingly, Eps15 contains three EH (Eps15-Homology) domains also found in proteins required for the internalization step of endocytosis in yeast. EH domains are required for correct coated pit targeting of Eps15. Furthermore, when cells express an Eps15 mutant lacking EH domains, the plasma membrane punctate distribution of both AP-2 and clathrin is lost, implying the absence of coated pits. This was further confirmed by the fact that dynamin, a GTPase found in coated pits, is homogeneously redistributed on the plasma membrane and that endocytosis of transferrin, a specific marker of clathrin-dependent endocytosis, is strongly inhibited. Altogether, these results suggest a role for Eps15 in coated pit assembly and more precisely a role for Eps15 in the docking of AP-2 onto the plasma membrane. This hypothesis is supported by the fact that a GFP fusion protein encoding the ear domain of alpha-adaptin, the AP-2 binding site for Eps15, is efficiently targeted to plasma membrane coated pits (Benmerah, 1999).
The role of amphiphysin in receptor-mediated endocytosis in vivo has been examined. To address the importance of the amphiphysin SH3 domain in dynamin recruitment, a transferrin and epidermal growth factor (EGF) uptake assay was carried out in COS-7 fibroblasts. Amphiphysin is present in these cells at a low level and indeed in other peripheral tissues. Confocal immunofluorescence revealed that cells transfected with the amphiphysin SH3 domain show a potent blockade in receptor-mediated endocytosis. To test whether the cellular target of amphiphysin is dynamin, COS-7 cells were contransfected with both dynamin and the amphiphysin SH3 domain; here, transferrin uptake was efficiently rescued. Importantly, the SH3 domains of Grb2, phospholipase C gamma and spectrin all fail to exert any effect on endocytosis. The mechanism of amphiphysin action in recruiting dynamin was additionally tested in vitro: amphiphysin can associate with both dynamin and alpha-adaptin simultaneously, further supporting a role for amphiphysin in endocytosis. These results suggest that the SH3 domain of amphiphysin recruits dynamin to coated pits in vivo, probably via plasma membrane adaptor complexes. It is proposed that amphiphysin is not only required for synaptic-vesicle endocytosis, but might also be a key player in dynamin recruitment in all cells undergoing receptor-mediated endocytosis (Wigge, 1997).
The synaptic vesicle protein synaptotagmin (see Drosophila Synaptotagmin) has been proposed to act as a major docking site for the recruitment of clathrin coats implicated in endocytosis, including the recycling of synaptic vesicles. The C2B domain of synaptotagmin binds mu2- and alpha-adaptin, two of the four subunits of the endocytic adaptor complex AP-2. mu2 represents the major interacting subunit of AP-2 within this complex. Its binding to synaptotagmin is mediated by a site in subdomain B that is distinct from the binding site for tyrosine-based sorting motifs located in subdomain A. The presence of the C2B domain of synaptotagmin at the surface of liposomes enhances the recruitment of AP-2 and clathrin. Conversely, perturbation of the interaction between synaptotagmin and AP-2 by synprint, the cytoplasmic synaptotagmin-binding domain of N-type calcium channels, inhibits transferrin internalization in living cells. It is concluded that a dual interaction of synaptotagmin with the clathrin adaptor AP-2 plays a key physiological role in the nucleation of endocytic clathrin-coated pits (Haucke, 2000).
Synaptojanin 1, a polyphosphoinositide phosphatase, is expressed as two major alternatively spliced isoforms of 145 kDa (SJ145) and 170 kDa (SJ170), which are thought to have pleiotropic roles in endocytosis, signaling and actin function. SJ145 is highly enriched in nerve terminals where it participates in clathrin-dependent synaptic vesicle recycling. SJ170, which differs from SJ145 by the presence of a carboxy-terminal extension, is the predominant isoform in developing neurons and is expressed in a variety of tissues. The carboxy-terminal domain unique to SJ170 binds Eps15, a protein involved in receptor-mediated endocytosis. The same domain also binds clathrin and the clathrin adaptor AP-2. These interactions occur both in vitro and in vivo and are direct. Binding of AP-2 is mediated by the ear domain of its alpha-adaptin subunit and binding of clathrin by the amino-terminal domain of its heavy chain. Overexpression in chinese hamster ovary (CHO) cells of full-length SJ170 or its unique carboxy-terminal region caused mislocalization of Eps15, AP-2 and clathrin, as well as inhibition of clathrin-dependent transferrin uptake. These findings suggest a close association of SJ170 with the clathrin coat and provide new evidence for its physiological role in the regulation of clathrin coat dynamics (Haffner, 2000).
RalBP1 and POB1, the downstream molecules of small GTP-binding protein Ral, are involved in receptor-mediated endocytosis together with Epsin and Eps15. The regulation of assembly of the complex of these proteins was examined. RalBP1, POB1, Epsin, and Eps15 formed a complex with alpha-adaptin of AP-2 in Chinese hamster ovary cells, but the formation is reduced in mitotic phase. RalBP1, POB1, Epsin, and Eps15 are all phosphorylated in mitotic phase. The phosphorylated forms of POB1 and Epsin are recognized by the antibody MPM2, which is known to detect mitotic phosphoproteins. POB1 and Epsin are phosphorylated by p34(cdc2) kinase in vitro. Their phosphorylation sites (Ser(411) of POB1 and Ser(357) of Epsin) were determined. Phosphorylated Epsin and Epsin(S357D) forms a complex with alpha-adaptin less efficiently than wild type Epsin. Although the EH domain of POB1 binds directly to Epsin, phosphorylation of Epsin inhibits the binding. Furthermore, Epsin(S357D) but not Epsin(S357A) has lost the effect of Epsin on the insulin-dependent endocytosis. These results suggest that phosphorylation of Epsin in mitotic phase inhibits receptor-mediated endocytosis by disassembly of its complex with POB1 and alpha-adaptin (Kariya, 2000).
Disabled-2 (Dab2) is a widely expressed relative of Disabled-1, a neuron-specific signal-transduction protein that binds to and receives signals from members of the low-density lipoprotein receptor (LDLR) family. Members of the LDLR family internalize through clathrin-coated pits and vesicles to endosomes, from where they return to the cell surface through the secretory pathway. In this study, the Dab2 phosphotyrosine-binding domain binds peptides containing the sequence FXN-PXY. This core sequence is found in the intracellular domains of LDLR family members and is important for receptor internalization. Dab2 transiently colocalizes with the LDLR in clathrin-coated pits, but is absent from endosomes and lysosomes. Dab2 is alternatively spliced and its localization depends on a region of the protein that contains two DPF motifs that are present in the p96 Dab2 protein and absent in the p67 splice variant. This region is sufficient to confer Dab2 binding to the alpha-adaptin subunit of the clathrin adaptor protein, AP-2. Overexpression of p96 but not of p67 Dab2 disrupts the localization of AP-2. These findings suggest that in addition to previously reported signal-transduction functions, Dab2 could also act as an adaptor protein that may regulate protein trafficking (Morris, 2001).
The adaptor proteins AP-2 and AP-1/GGAs are essential components of clathrin coats at the plasma membrane and trans-Golgi network, respectively. The adaptors recruit accessory proteins to clathrin-coated pits, which is dependent on the adaptor ear domains engaging short peptide motifs in the accessory proteins. An extensive mutational analysis was performed of a novel WXXF-based motif that functions to mediate the binding of an array of accessory proteins to the alpha-adaptin ear domain of AP-2. Using nuclear magnetic resonance and mutational studies, WXXF-based motifs were identified as major ligands for a site on the alpha-ear previously shown to bind the DPW-bearing proteins epsin 1/2. The determinants that allow for specific binding of the alpha-ear motif to AP-2 were defined as compared to those that allow a highly related WXXF-based motif to bind to the ear domains of AP-1/GGAs. Intriguingly, placement of acidic residues around the WXXF cores is critical for binding specificity. These studies provide a structural basis for the specific recruitment of accessory proteins to appropriate sites of clathrin-coated vesicle formation (Ritter, 2004).
The AP-2 adaptor complex plays a key role in cargo recognition and clathrin-coated vesicle formation at the plasma membrane. To investigate the functions of individual binding sites and domains of the AP-2 complex in vivo, transfected HeLa cells were transfected with wild-type and mutant small interfering RNA-resistant alpha and mu2 subunits and then siRNA knockdowns were used to deplete the endogenous proteins. Mutating the PtdIns(4,5)P2 binding site of alpha, the phosphorylation site of mu2, or the YXXPhi binding site of mu2 impairs AP-2 function, as assayed by transferrin uptake. In contrast, removing the C-terminal appendage domain of alpha, or mutating the PtdIns(4,5)P2 binding site of mu2, has no apparent effect. However, adding a C-terminal GFP tag to alpha renders it completely nonfunctional. These findings demonstrate that there is some functional redundancy in the binding sites of the various AP-2 subunits, because no single mutation totally abolishes function. They also help to explain why GFP-tagged AP-2 never appears to leave the plasma membrane in some live cell imaging studies. Finally, they establish a new model system that can be used both for additional structure-function analyses, and as a way of testing tagged constructs for function in vivo (Motley, 2006; full text of article).
The AP-2 adaptor complex plays a key role in cargo recognition and clathrin-coated vesicle formation at the plasma membrane. To investigate the functions of individual binding sites and domains of the AP-2 complex in vivo, transfected HeLa cells were transfected with wild-type and mutant small interfering RNA-resistant alpha and mu2 subunits and then siRNA knockdowns were used to deplete the endogenous proteins. Mutating the PtdIns(4,5)P2 binding site of alpha, the phosphorylation site of mu2, or the YXXPhi binding site of mu2 impairs AP-2 function, as assayed by transferrin uptake. In contrast, removing the C-terminal appendage domain of alpha, or mutating the PtdIns(4,5)P2 binding site of mu2, has no apparent effect. However, adding a C-terminal GFP tag to alpha renders it completely nonfunctional. These findings demonstrate that there is some functional redundancy in the binding sites of the various AP-2 subunits, because no single mutation totally abolishes function. They also help to explain why GFP-tagged AP-2 never appears to leave the plasma membrane in some live cell imaging studies. Finally, they establish a new model system that can be used both for additional structure-function analyses, and as a way of testing tagged constructs for function in vivo (Motley, 2006; full text of article).
Upon activation by Wnt, the Frizzled receptor is internalized in a process that requires the recruitment of Dishevelled. A novel interaction is described between Dishevelled2 (Dvl2) and μ2-adaptin, a subunit of the clathrin adaptor AP-2; this interaction is required to engage activated Frizzled4 with the endocytic machinery and for its internalization. The interaction of Dvl2 with AP-2 requires simultaneous association of the DEP domain and a peptide YHEL motif within Dvl2 with the C terminus of μ2. Dvl2 mutants in the YHEL motif fail to associate with μ2 and AP-2, and prevent Frizzled4 internalization. Corresponding Xenopus Dishevelled mutants show compromised ability to interfere with gastrulation mediated by the planar cell polarity (PCP) pathway. Conversely, a Dvl2 mutant in its DEP domain impaired in PCP signaling exhibits defective AP-2 interaction and prevents the internalization of Frizzled4. It is suggested that the direct interaction of Dvl2 with AP-2 is important for Frizzled internalization and Frizzled/PCP signaling (Yu, 2007).
Based on four independent lines of evidence, it is proposed that a tight association between Dishevelled and AP-2 is important for at least some of the known biological functions of Dishevelled. One involves the observation that Frizzled4 is rapidly internalized upon its activation by Wnt, a process that requires Dvl2. This rapid and efficient uptake is coupled to Frizzled degradation, presumably in lysosomes, and both processes are greatly hindered in cells expressing variants of Dvl2 that fail to interact with AP-2 by virtue of selected point mutations in the YHEL motif or the DEP domain. It is suggested that proper engagement of Dvl2 with AP-2 is a key step for Frizzled4 endocytosis and its eventual degradation. It is possible that, under certain conditions, Dvl2 engages productively with the endocytic machinery by associating with β-arrestin2, which in turn can bind to clathrin and AP-2, as shown by failure to internalize Frizzled4 in cells depleted of β-arrestin2 by siRNA treatment. It seems, however, that the interaction of Dvl2 and β-arrestin2 can be superseded, because a block is observed in Frizzled4 endocytosis upon expression of Dvl2 mutants in the tyrosine motif that, according to a pull-down assay, bind β-arrestin2 perfectly well (Yu, 2007).
The second line of evidence involves Wnt signaling during frog embryonic development. Frog Xdsh has important regulatory roles in the canonical β-catenin and the noncanonical PCP pathways. Experiments, carried out in developing embryos, show that Xdsh with single-point mutations in its YHEL motif induces dorsal axis duplication as well as does the wild-type Xdsh, indicating that the mutations have little or no effect on the function of Xdsh in regulating the canonical β-catenin pathway. In contrast, presence of the YHEL motif is required for proper regulation of the noncanonical PCP pathway. This conclusion is based on the observation that overexpression of the wild-type Xdsh interferes with gastrulation in embryos and with elongation in the animal cap assay, whereas these processes are largely normal with any one of the YHEL mutant forms of Xdsh expressed at similar levels (Yu, 2007).
The third and fourth lines of corroborating evidence were obtained by following the effects of the Xdsh/Dvl2 mutants on two independent molecular signaling assays, one based on the activation of JNK in frog embryos, one of the hallmarks of PCP signaling, and the other based on stimulation of the TOPFlash reporter assay in mammalian cells, an indication of signaling through the canonical Wnt pathway. Xdsh, but none of the YHEL mutants, stimulated JNK, reflecting their failure to activate the noncanonical pathway; in contrast, both wild-type and Dvl2 mutants stimulated equally the TOPFlash assay, reflecting their comparable signaling through the canonical pathway. A possible caveat to the interpretation of these results is the fact that they involved gain of function effects by overexpression of mutant Dishevelled, rather than strict replacement of endogenous Dishevelled with the mutant forms. The latter experiment is currently not feasible, given the functional redundancy among different members of the Dishevelled family (Yu, 2007).
AMPA-type glutamate receptors undergo constitutive and ligand-induced internalization that requires dynamin and the clathrin adaptor complex AP-2. An atypical basic motif within the cytoplasmic tails of AMPA-type glutamate receptors directly associates with mu2-adaptin by a mechanism similar to the recognition of the presynaptic vesicle protein synaptotagmin 1 by AP-2. A synaptotagmin 1-derived AP-2 binding peptide competes the interaction of the AMPA receptor subunit GluR2 with AP-2mu and increases the number of surface active glutamate receptors in living neurons. Moreover, fusion of the GluR2-derived tail peptide with a synaptotagmin 1 truncation mutant restores clathrin/AP-2-dependent internalization of the chimeric reporter protein. These data suggest that common mechanisms regulate AP-2-dependent internalization of pre- and post-synaptic membrane proteins (Kastning, 2007).
The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs; see Drosophila NMDA receptors) internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 (see Drosophila Scribbled) is a large PDZ protein required for synaptogenesis and synaptic plasticity. This study shows that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, it was shown that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, these findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling (Piguel, 2014).
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