Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

MAGI2/S-SCAM

  • Xiaoyin Xu
  • Manami Kodaka
  • Hiroaki Iwasa
  • Yutaka Hata
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101774

Synonyms

Historical Background

MAGI stands for membrane-associated guanylate kinase with an inverted arrangement of protein-protein interaction domains. Human genome has three MAGI genes (MAGI1, MAGI2, and MAGI3). The encoded proteins belong to the membrane-associated guanylate kinases (MAGUKs) and are collectively called MAGI family proteins. Other MAGUKs, such as ZO-1, PSD-95, and CASK, harbor the guanylate kinase (GK) domain in the C-terminal region, while MAGI family proteins have the GK domain in the N-terminal region (Funke et al. 2005). For this, MAGI family proteins are claimed to have an inverted arrangement of protein-protein interaction domains. Human MAGI2, rat MAGI2, and mouse MAGI2 were identified as an interacting protein with atrophin-1, synapse-associated protein 90-associated proteins (SAPAPs), and activin receptor, respectively (Wood et al. 1998; Hirao et al. 1998; Shoji et al. 2000). Accordingly, they were named by researchers as atrophin-1-interacting protein 1 (AIP1), synaptic scaffolding protein (S-SCAM), and activin receptor-interacting protein 1 (ARIP1). The gene symbols MAGI2 and Magi2 were assigned to these genes. As MAGI2 has been extensively studied as a synaptic protein, the term “S-SCAM” is still frequently used in the field of neuroscience.

The Molecular Structure

Human MAGI2 and mouse Magi2 are composed of numerous exons and several variants with alternated exons are known. Mouse MAGI2 isoform 1, the longest one, is composed of six PDZ domains (PDZ0–PDZ5), one GK domain, and two WW domains, while isoform 2 starts with the different initiation site in the GK domain (Fig. 1). Human MAGI2 has an extended C-terminus compared with mouse MAGI2.
MAGI2/S-SCAM, Fig. 1

Molecular structure of mouse MAGI2. Mouse MAGI2 isoform 1 has six PDZ domains (PDZ), one guanylate kinase (GK) domain, and two WW domains (WW). Isoform 2 lacks the first PDZ domain and the N-terminal half of the GK domain. The knockout mice lacking MAGI2 isoform 1 is lethal. Despite the expression of MAGI2 isoform 2, they have abnormal phenotypes at dendritic spines in the brain and exhibit proteinuria. These findings indicate that MAGI2 isoform 1 is essential for the formation of excitatory synapses and the slit diaphragm

The Interacting Molecules

MAGI2 interacts with various proteins via GK, WW, and PDZ domains and functions as a scaffold protein. The list of MAGI2-interacting molecules includes receptors (N-methyl-D-aspartate receptors subunit 2 (NMDAR2), δ2-glutamate receptor, β1-aderenergic receptors, etc.), cell adhesion molecules (neuroligin, nephrin, etc.), regulators of signals (phosphatase and tensin homolog (PTEN), RAPGEF2, etc.), and other membrane-associated proteins (SAPAP, β-catenin, etc.) (Table 1) (Hirao et al. 1998; Yap et al. 2003; Xu et al. 2001; Lehtonen et al. 2005; Wu et al. 2000; Ohtsuka et al. 1999; Nishimura et al. 2002; Kawajiri et al. 2000).
MAGI2/S-SCAM, Table 1

MAGI2-interacting molecules

Transmembrane proteins

N-methyl-D-glutamate receptor

δ2 Glutamate receptor

β1-Adrenergic receptor

Vasoactive intestinal peptide 1 type-1 receptor (VPAC1)

Brain-specific angiogenesis inhibitor-1 (BAI1)

Activin Type II receptors

ERBB4

Neuroligins

β-Dystroglycan

Dendrite arborization and synapse maturation 1 (Dasm1)/IgSF9

IgSF9b

Nectin

Delta1

Scaffold proteins, adaptor proteins, and cytoskeleton-associated proteins

Synapse-associated protein 90-associated proteins (SAPAP)/Guanylate kinase-associated protein (GKAP)

MAGUK-interacting protein (MAGUIN)/connector enhancer of ksr2 (Cnk2)

Postsynaptic density-95 (PSD-95)/synapse-associated protein 90 (SAP90)

Tamalin/general receptor for phosphoinositides 1-assoicated scaffold protein (GRASP)

Transmembrane AMPA receptor regulating proteins (TARPs)

SANS

Dendrin

Afadin

Atrophin-1

β-Catenin

δ-Catenin

Signaling molecules

Phosphatase and tensin homolog (PTEN)

RAPGEF2

SynArfGEF

SMAD2/3

Axin

MAGI2 as a Synaptic Scaffold Protein

MAGI2 expression is very high in the brain (Hirao et al. 1998). MAGI2 is expressed at excitatory and inhibitory synapses (Hirao et al. 1998; Sumita et al. 2007). A number of proteins interact with MAGI2 at synapses. As those proteins bind to different sequences of MAGI2, it is surmised that MAGI2 simultaneously interacts with them to form a functional complex and to facilitate signalings, so that distinct synaptic subdomains are linked and integrated into mature synapses.

β-catenin, which is associated with N-cadherin, binds MAGI2 and recruits it to synapses (Nishiumura et al. 2002). MAGI2 induces the clustering of neuroligin at excitatory synapses, while the deletion mutant of MAGI2 containing the neuroligin-binding region disturbs the synaptic localization of neuroligin in a dominant-negative manner, supporting that MAGI2 determines the localization of neuroligin (Iida et al. 2004). Neuroligin localization at synapses depends on N-cadherin (Stan et al. 2010). MAGI2 is considered to be a key molecule that links N-cadherin and neuroligin. MAGI2 mutant also influences the synaptic accumulation of PSD-95 via neuroligin (Iida et al. 2004). MAGI2 as well as PSD-95 interacts with NMDAR2 and causes the clustering of NMDAR (Hirao et al. 1998). In MAGI2 knockout mice, NMDAR-mediated RhoA activation is compromised and dendritic spines exhibit elongated phenotypes (Iida et al. 2007). These findings imply that MAGI2 is instrumental for the organization of excitatory synapses, which is initiated with the cadherin-dependent cell adhesion (Fig. 2).
MAGI2/S-SCAM, Fig. 2

Roles of MAGI2 at excitatory synapses. MAGI2 is recruited to dendritic spines via the interaction of β-catenin. MAGI2 induces the clustering of neuroligin and subsequently accumulates PSD-95. MAGI2 regulates the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor) via transmembrane AMPA receptor regulating proteins (TARPs). PSD-95 is a synaptic membrane-associated guanylate kinase that interacts with N-methyl-D-aspartate glutamate receptor (NMDA receptor) and neuroligin. PSD-95 also regulates AMPA receptors. MAGI2 and PSD-95 are similar in the molecular structure and the interacting molecules but have distinct characters. MAGI2 interacts with β-catenin but PSD-95 does not. MAGI2 is expressed at both excitatory and inhibitory synapses, while PSD-95 is exclusively localized at excitatory synapses. Although not shown in this figure, other molecules such as tamalin, dendrin, and Dendrite arborization and synapse maturation 1 (Dasm1) /Igsf9 also interact with MAGI2 at the excitatory synapses. N-cadherin mediates hemophilic cell adhesion, whereas neuroligin binds to neurexin that is expressed at presynaptic membrane. MAGI2 is considered to link subsynaptic regions containing cadherin and neuroligin/neurexin

MAGI2 also plays a role in synapse maturation. MAGI2 interacts with the transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) regulating proteins (TARPs), which control AMPAR trafficking (Deng et al. 2006) (Fig. 2). Forced expression of MAGI2 increases synaptic AMPAR and enhances AMPAR-mediated synaptic transmission. Conversely, MAGI2 depletion reduces surface AMPAR expression (Deng et al. 2006). The interference in the interaction between MAGI2 and TARPs abolishes the effect of MAGI2 on surface AMPAR expression, supporting that MAGI2 regulates AMPAR via TARPs. To note, MAGI2 specifically affects AMPAR containing GluR2 subunit and makes a contrast with PSD-95, which regulates AMPAR through GluA1 subunit (Danielson et al. 2012a, b). Dendrite arborization and synapse maturation 1 (Dasm1)/Igsf9 is a cell adhesion molecule of immunoglobulin superfamily with a PDZ-binding motif (Shi et al. 2004a). Dasm1/Igsf9 knockdown and dominant-negative mutants reduce AMPAR-mediated transmission but not NMDAR-mediated transmission (Shi et al. 2004b). Although the interaction between MAGI2 and Dasm1/Igs9 is not confirmed at the endogenous level, the potential role of MAGI2 in the regulation by Dasm1/Igsf9 of AMPAR was discussed (Shi et al. 2004b). GluRδ2 is expressed at synapses formed by parallel fibers and Purkinje cells in cerebellum and is important in long-term depression (LTD) (Landsend et al. 1997). GluRδ2 belongs to the ionotrophic glutamate receptor family, but the channel function is dispensable for GluRδ2 to regulate LTD, while the interaction with PDZ-binding proteins is essential (Kohda et al. 2007). As the interaction between MAGI2 and GluRδ2 is enhanced by the protein kinase C (PKC)-mediated phosphorylation of GluRδ2 and PKC is crucial for LTD, MAGI2 is surmised to be important in the regulation of LTD.

At the inhibitory synapses, MAGI2 interacts with neuroligin 2, β-dystroglycan, and Igsf9b, which is similar to but distinct from Dasm/Igsf9 (Sumita et al. 2007; Woo et al. 2013). Neuroligin 2 clusters gephyrin but Igsf9b does not. It means that Igsf9b is localized at a subsynaptic domain different from gephyrin-GABA receptor-containing domain. MAGI2 forms a ternary complex with Igsf9b and neuroligin 2 and links two distinct domains at inhibitory synapses (Woo et al. 2013). Furthermore, MAGI2 is likely to link neuroligin 2 to the dystroglycan complex (Sumita et al. 2007). These observations suggest that MAGI2 is a key molecule in the organization of inhibitory synapses (Fig. 3).
MAGI2/S-SCAM, Fig. 3

Roles of MAGI2 at inhibitory synapses. Human has four neuroligin genes. Among them, neuroligin 2 is specifically expressed at inhibitory synapses. MAGI2 interacts with β-dystroglycan, Igsf9b, and neuroligin 2 at the inhibitory synapses. Neuroligin 2 induces the clustering of gephyrin, which in turn induces γ-aminobutyric acid (GABA) receptor clustering. Neuroligin 2 and dystroglycan complex transsynaptically interact with neurexin. Igsf9b is a hemophilic cell adhesion molecule. MAGI2 is considered to link subsynaptic regions containing Igsf9b, neurexin/dystroglycan, and neuroligin/neurexin. There is no information regarding the order in which Igsf9b, MAGI2, β-dystroglycan, and neuroligin 2 are assembled at inhibitory synapses. The interactions are depicted by double-headed arrows. MAGI2 interacts with SynArfGEF (not shown in this figure). As SynArfGEF is a regulator of Arf6, MAGI2 may be implicated in the regulation of endocytosis at inhibitory synapses

MAGI2 and Membrane Traffics in Neurons

As the interaction with TARPs exemplifies, MAGI2 is closely related to the regulatory machinery of membrane traffics in neurons. Tamalin (also called general receptor for phosphoinositides 1-associated protein (GRASP)) is known to promote trafficking and cell-surface expression of group 1 metabotropic glutamate receptors (Kitano et al. 2002). KIF1B is a kinesin superfamily motor protein that plays a role in the transport of synaptic vesicles (Nangaku et al. 1994). SynArfGEF is an activator of Arf6 and is expressed at inhibitory synapses (Inaba et al. 2004). SynArfGEF promotes the endocytosis of transferrin receptors. CIN85 is a well-known regulator of the clathrin-dependent endocytosis of various receptors and is expressed at excitatory synapses (Soubeyran et al. 2002; Kawata et al. 2006). MAGI2 interacts with these proteins directly or indirectly (in the case of CIN85, the interaction is mediated by dendrin), though the physiological significance is not yet clear for all interactions (Kawata et al. 2006; Kitano et al. 2003; Mok et al. 2002; Fukaya et al. 2011). More particularly, it is demonstrated that MAGI2 enhances the agonist-induced endocytosis of β1-aderenregic receptor (Xu et al. 2001).

MAGI2 and Neurological Diseases

The links between MAGI2 and neurological diseases have been duly reported. Implicated infantile spasms-associated genes are predicted to be on chromosome 7q11.23-q21.11 (Marshall et al. 2008). MAGI2 is encoded in this region and attracts attention as a candidate. Indeed, deletion of MAGI2 is detected in patients with infantile spasms (Peterson et al. 2014). There is also an inconsistent report that certain patients have deletions outside MAGI2 in the 7q11.23-q21.11 (Röthlisberger et al. 2010). Yet, it is possible that such deletions influence MAGI2 expression, and further studies are required. Duplication of MAGI2 was found in childhood-onset schizophrenia (Walsh et al. 2008). Transgenic mice harboring extra copies of MAGI2 exhibit schizophrenic behaviors (Zhang et al. 2015). The association between common single nucleotide polymorphisms of MAGI2 and schizophrenia in Japanese was also investigated (Koide et al. 2012). The study did not support strong association but suggested the association between MAGI2 and cognitive impairment in schizophrenic patients.

MAGI2 as a Tumor Suppressor

Phosphatase and tensin homolog (PTEN) functions as a tumor suppressor by negatively regulating Akt pathway (Worby and Dixon 2014). Mutations and deletions of PTEN are frequently detected in human cancers. The yeast two-hybrid screening by use of human prostate cDNA library revealed MAGI2 as a PTEN-interactor (Wu et al. 2000). Importantly, MAGI2 stabilizes PTEN and enhances its expression (Tolkacheva et al. 2001). Rearrangements disrupting MAGI2 are detected in human cancers (Berger et al. 2011). MAGI2 expression is downregulated in prostate cancer cell lines and clinical prostate cancer samples (Mahdian et al. 2014). MAGI2 is hypermethylated in cervical cancers (Chen et al. 2014). Papillomavirus E6 oncoprotein targets MAGI2 for degradation (Thomas et al. 2002). MAGI2, when exogenously expressed in hepatocellular carcinoma cells, inhibits cell migration and proliferation and enhances staurosporine-induced apoptosis via PTEN (Hu et al. 2007). Conversely, the downregulation of MAGI2 by miR-134/487b/655 contributes to the transforming growth factor β1-induced resistance against gefitinib in lung adenocarcinoma cells (Kitamura et al. 2014). In breast cancer MCF-7 cells, which express estrogen receptors and respond to antiestrogen therapy, miR-101 targets MAGI2, reduces PTEN activity, upregulates Akt, and enables estrogen-independent growth (Sachdeva et al. 2011). All these data indicate that MAGI2 is a tumor suppressor and that its deregulation is important in the pathophysiology of human cancers.

MAGI2 as an Essential Component of Slit Diaphragm

Nephrin is a cell adhesion molecule of immunoglobulin superfamily and forms the slit diaphragm between podocytes in kidney glomerulus (Kestilä et al. 1998). The slit diaphragm works as a renal filtration barrier, and the disruption causes proteinuria. Nephrin gene, NPHPS1, was identified as a mutated gene in the congenial nephrotic syndrome of the Finnish type (Kestilä et al. 1998). MAGI2 was identified as a nephrin-interacting protein in the pull-down assay by use of glutathione S-transferase-fused nephrin (Lehtonen et al. 2005). Later, MAGI2 turned out to be a target gene of Wilm’s tumor suppressor gene 1 (WT1), which is a key regulator in kidney development (Dong et al. 2015; Lefebvre et al. 2015). The importance of MAGI2 in the slit diaphragm is underscored by three lines of MAGI2 knockout mice (Lefebvre et al. 2015; Balbas et al. 2014; Ihara et al. 2014). The reported phenotypes are not the same, but all knockout mice develop proteinuria, supporting that MAGI2 is an essential component of slit diaphragm.

MAGI2 and Intestine

The role of MAGI2 in the intestine was first noticed in the study regarding vasoactive intestinal peptide (VIP), which regulates fluid and electrolyte secretion in the gastrointestinal system (Gee et al. 2009). MAGI2 binds to VIP1 type-1 receptor (VPAC1) and inhibits VPAC1-mediated cAMP production and VPAC1 endocytosis (Gee et al. 2009). Thereafter, based on the hypothesis that variants of tight junction genes influence epithelial cell barrier and correlate with the occurrence of coeliac disease and inflammatory bowel disease, the association of genetic variations of MAGI2 with these diseases was investigated (Wapenaar et al. 2008; McGovern et al. 2009). The studies have revealed the association of certain variants with coeliac disease, ulcerative colitis, and Crohn’s disease.

MAGI2 and Other Interacting Molecules

Besides the above-mentioned molecules, MAGI2 is reported to interact with miscellaneous molecules, though the physiological relevance of all interactions is not fully tested. MAGI2 interacts with activin type II receptors and Smad3 and inhibits activin-induced transcription (Shoji et al. 2000). MAGI2 interacts with kinase D-interacting substrate 220 kDa (KIDINS220) and RAPGEF2 (Hisata et al. 2007). MAGI2 forms a complex with KIDINS220 and RAPGEF2 under the basal condition, but KIDINS220 binds to TrkA in response to nerve growth factor (NGF). In this way, MAGI2 mediates the recruitment of RAPGEF2 to the late endosomes containing TrkA after NGF stimulation, sustains Rap1 activation, and eventually leads to neurite outgrowth (Hisata et al. 2007). MAGI2 binds ERBB4 and is tyrosine-phosphorylated, but how MAGI2 affects ERBB4 signal is not yet studied (Buxbaum et al. 2008). In podocytes, MAGI2 binds Vangl2, which is involved in the planar cell polarity (PCP), and may mediate the PCP signaling that regulates podocyte morphology (Babayeva et al. 2011). The human Usher syndrome is a ciliopathy that affects vision and hearing (Mathur and Yang 2015). USH1G is one of the Usher syndrome-associated genes and encodes a scaffold protein SANS. SANS interacts with MAGI2 and inhibits MAGI2-mediated transferrin receptor endocytosis (Bauß et al. 2014). In mouse inner medullary collecting duct IMCD3 cells, knockdown of Magi2 as well as that of Ush1g abolishes ciliogenesis. MAGI2 was detected as a binding partner of the C-terminus of human Delta1, although the physiological meaning was not studied in mammalian cells (Wright et al. 2004). The interactions of MAGI2 with nectin, a cell adhesion molecule, and with afadin, a membrane-associated scaffold protein, are also proposed at the puncta adherens junction in hippocampal CA3 region (Yamada et al. 2003).

Summary

Many proteins are reported to interact with MAGI2. It is not surprising, because MAGI2 harbors multiple protein-protein interaction modules, especially PDZ domains. We have to carefully evaluate which molecules are bona fide interactors. The specificity of the interaction mediated by the PDZ domain is not high. Coimmunoprecipitation of endogenous proteins does not necessarily guarantee the physiological relevance of the interaction, unless the colocalization is confirmed in vivo. Even so, the interactions of MAGI2 that we have discussed here are well supported by experiments, and the importance of MAGI2 in the organization of synapses and kidney slit diaphragm is obvious. The studies of the association of MAGI2 variations with human diseases will be insightful to understand the physiological role of MAGI2. A recent study has revealed that the methylation status of MAGI2 is different between monozygotic twins with or without type I diabetes (Elboudwarej et al. 2016). In patients with chronic obstructive pulmonary diseases, higher MAGI2 expression in bronchus is associated with less inflammation (Dijkstra et al. 2015). Currently, there is no explanation for why MAGI2 is associated with these diseases. Further studies are awaited.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Xiaoyin Xu
    • 1
    • 2
  • Manami Kodaka
    • 1
  • Hiroaki Iwasa
    • 1
  • Yutaka Hata
    • 1
    • 3
  1. 1.Department of Medical Biochemistry, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Department of Breast SurgeryThe Second Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
  3. 3.Center for Brain Integration ResearchTokyo Medical and Dental UniversityTokyoJapan