Erbb1-4-Dependent EGF/Neuregulin Signals and Their Cross Talk in the Central Nervous System: Pathological Implications in Schizophrenia and Parkinson’S Disease

REVIEW ARTICLE published: 13 February 2013 CELLULAR NEUROSCIENCE doi: 10.3389/fncel.2013.00004 ErbB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson’s disease

Yuriko Iwakura*andHiroyuki Nawa

Division of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

Edited by: Ligands for ErbB1-4 receptor tyrosine kinases, such as epidermal growth factor (EGF) Chao Deng, University of and neuregulins, regulate brain development and function. Thus, abnormalities in their Wollongong, Australia signaling are implicated in the etiology or pathology of schizophrenia and Parkinson’s Reviewed by: disease. Among the ErbB receptors, ErbB1, and ErbB4 are expressed in dopamine Corette Wierenga, Utrecht University, Netherlands and GABA neurons, while ErbB1, 2, and/or 3 are mainly present in oligodendrocytes, Claudia Lodovichi, Venetian Institute astrocytes, and their precursors. Thus, deﬁcits in ErbB signaling might contribute to the of Molecular Medicine, Italy neurological and psychiatric diseases stemming from these cell types. By incorporating *Correspondence: the latest cancer molecular biology as well as our recent progress, we discuss signal Yuriko Iwakura, Division of cross talk between the ErbB1-4 subunits and their neurobiological functions in each cell Molecular Neurobiology, Brain Research Institute, Niigata type. The potential contribution of virus-derived cytokines (virokines) that mimic EGF and University, 1-757 Asahimachi, neuregulin-1 in brain diseases are also discussed. Niigata 951-8585, Japan. e-mail: [email protected] Keywords: ErbB1-4, dopamine, GABA, virokine, schizophrenia, Parkinson’s disease

INTRODUCTION (Downward et al., 1984). Following this discovery, homologous ErbB molecules are membrane-spanning receptor tyrosine gene cloning led to the identification of the other of ErbB fam- kinases that act on epidermal growth factor (EGF) and its deriva- ily members, including ErbB2 (HER2, Neu), ErbB3 (HER3), and tives. The ErbB family consists of four members, ErbB1, B2, ErbB4 (HER4) (Schechter et al., 1984; Semba et al., 1985; Kraus B3, and B4, that were originally identified in vertebrates (mam- et al., 1989; Plowman et al., 1993). This family shares 40–50% mals) and share significant structural homology with mem- structural homology in the extracellular domains and 60–80% in bers of the ErbB family (Downward et al., 1984; Schechter the intracellular domains (Figure 2, Table 1). et al., 1984; Semba et al., 1985; Kraus et al., 1989; Plowman et al., 1993). ErbB1 homolog is identified also in invertebrates, THE MOLECULAR FEATURES OF THE ErbB FAMILY C. elegans (LET-23; Aroian et al., 1990) and Drosophila (DER; Ligands for ErbB receptors can be classified into two groups: Schejter and Shilo, 1989). ErbB receptor family members are the EGF family and the NRG family (Falls, 2003; Higashiyama distributed in many organs and cell types originating from et al., 2008; Mei and Xiong, 2008). The EGF family consists of ectodermal and mesodermal tissues and have functions in var- transforming growth factor alpha (TGFα; Derynck et al., 1984), ious cellular processes/functions such as proliferation, growth, heparin-binding EGF-like growth factor (HB-EGF; Higashiyama migration, and adhesion. Upon binding to its ligand such et al., 1991), amphiregulin (AR; Shoyab et al., 1989), epireg- as EGF and neuregulin-1 (NRG1), the ErbB receptor under- ulin (EPR; Toyoda et al., 1995), betacellulin, (BTC; Sasada et al., goes tertiary structural alterations in the juxtamembrane region 1993; Shing et al., 1993), and epigen (EPG; Strachan et al., 2001). and increases its affinity for another an ErbB molecule, lead- The NRG family includes NRG1 (Brockes and Kintner, 1986; ing to homo- or heterodimerization (Olayioye et al., 2000). Holmes et al., 1992; Peles et al., 1992; Falls et al., 1993; Ho et al., This dimerization allows the kinase domain to phosphorylate 1995), NRG2 (NTAK; Higashiyama et al., 1997), NRG3, NRG4 the ErbB partner. The phosphorylated tyrosine residues recruit (Hobbs et al., 2002), NRG5 (tomoregulin; Uchida et al., 1999), adaptor/effecter molecules, such as phosphatidylinositol 3-kinase and NRG6 (neuroglycan C; Kinugasa et al., 2004). Most of these (PI3K) subunit p85, Src, and Shc, and transmit signals to ligands are initially synthesized as large membrane-anchored pre- these transducers. As overexpression of ErbB receptors results cursors that are processed into secretable and soluble forms and in ligand-independent dimerization and auto-phosphorylation, then liberated into the extracellular space where they interact receptor dimerization, rather than the activation of the kinase with ErbB receptors (Figure 2). In contrast to this process of domain, is thought to limit ErbB signaling (i.e., phosphorylation) “endocrine signaling,” these precursors are also thought to medi- (Figure 1). ate “juxtacrine signaling” during cell–cell communication; the The primary structure of ErbB1 (EGFR, HER1) was first eluci- membrane-anchored precursors directly bind to ErbB receptors dated among ErbBs. The oncogene v-erbB was identified in avian on the other side of the cell surface (Ono et al., 1994). Please read erythroblastic leukemia virus. The ortholog and proto-oncogene the details of “juxtacrine signaling” in other reviews (Iwamoto of c-erbB was determined to be the gene for EGF receptor, erbB1 and Mekada, 2000; Singh and Harris, 2005).

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FIGURE 1 | ErbB receptor dimerization and activation. The ligand domain and allows it to phosphorylate the cytoplasmic region of the ErbB interaction with ErbB 1, 3, and 4 increases their afﬁnity and induces homo- or partner. The phosphorylated tyrosine residues recruit various heterodimerization of ErbB1-4. This dimerization activates the tyrosine kinase adaptors/effectors that induce intracellular signals.

FIGURE 2 | ErbB receptors and their ligands. The molecular structure of ErbB receptors and proteolytic processing of their ligands are displayed.

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Table 1 | ErbB molecules and their ligands and adaptors/effectors.

ErbB receptor Nomenclature Binding partner Ligand Major signaling molecules Other binding proteins

ErbB1 EGF receptor ErbB1 EGF EPG PI3K-AKT Cbl (EGFR), HER1 ErbB2 TGFα EPR Ras-MAPK STAT3 ErbB3 HB-EGF PLCγ-PKC ErbB4 AR Crk FAK JAK BTC Src PTEN

ErbB2 Neu, HER2 ErbB1 Unknown PI3K-AKT Erbin ErbB3 Ras-MAPK ErbB4 FAK Src

ErbB3 HER3 ErbB1 NRG1 PI3K-AKT Cbl ErbB2 NRG2 Ras-MAPK EBP1 ErbB4 NRG6 PLCγ-PKC TENC1 CrkITKJAKLynSrcVAV

ErbB4 HER4 ErbB1 HB-EGF NRG2 PI3K-AKT N-Cor ErbB2 BTC NRG3 Ras-MAPK PSD95 ErbB3 EPG NRG4 JAK Src Ptprz STAT5 ErbB4 NRG1 NRG5 TAB2

Among the ErbB receptors, ErbB3 lacks the active kinase et al., 2001; Vidal et al., 2005; Sundvall et al., 2007; Lin et al., 2008; domain and is unable to phosphorylate ErbB in this dimer com- Xia et al., 2011; Ward et al., 2012). plex. However, upon ligand binding, ErbB3 associates with the heterodimer complex containing the other ErbB and is phospho- CELL SIGNALING AND FUNCTIONS OF INDIVIDUAL ErbB rylated by the partner ErbB kinase, leading to signal transduction MOLECULES by ErbB3 (Sierke et al., 1997). Conversely, ErbB2 harbors an active All ErbB molecules are expressed not only in peripheral tissues kinase domain, but its high-affinity ligands remain unknown but also in various neural cells (Table 2). In the view of their func- (Cho et al., 2003; Garrett et al., 2003). The ErbB1 and ErbB2 tionality in the brain, we need to consider which ErbB subtype is genes are often amplified and overexpressed in various cancer expressed, where it is expressed, and with which ErbB molecule it cells, resulting in self-dimerization and auto-phosphorylation colocalizes or dimerizes. As discussed above, the phosphorylated in a ligand-independent manner. For instance, ErbB2 is ampli- ErbB partner determines the functional nature of signaling, irre- fied in 3% of lung cancers, 30% of breast cancers, 20% of spective of the ErbB ligand. In this context, it is not true that NRG gastric cancers, and 60% of ovarian cancers. The combination only evokes the signals of its receptor, ErbB3 and/or ErbB4. of the ErbB1-4 subunits during heterodimerization does not appear to be limited; NRG1-bound ErbB4 can associate with ErbB1 (EGFR, HER1) ErbB1 to form a heterodimer, even though ErbB1 is not acti- ErbB1 signaling links to a large variety of cellular functions, vated by EGF (Liu et al., 2012). NRG1 mimics EGF signaling such as cell survival and proliferation. The down-stream signals through ErbB1 phosphorylation in ErbB4:ErbB1 heterodimer linked to ErbB include the phospholipase Cγ (PLCγ)- protein complexes. In the ErbB4:ErbB1 heterodimer, NRG promotes kinase C (PKC), Ras- mitogen-activated protein kinase (MAPK), more threonine phosphorylation and less tyrosine phosphory- PI3K-Akt, and janus kinase 2 (JAK2)-STAT3 pathways (Figure 3). lation of ErbB1, which results in Shc/Grb2 recruitment, than The Ras-MAPK pathway is implicated in cell proliferation and does EGF (Olayioye et al., 1998). Therefore, even within the differentiation, while the PI3K-Akt pathway is involved in cell context of the same heterodimer, distinct ligands can differen- growth and anti-apoptotic processes and the PLCγ-PKC pathway tially impact receptor signaling (Moghal and Sternberg, 1999). contributes to cell migration and division. The subcellular local- Of note, external stimuli can also affect partnership during ErbB ization and protein levels of these adaptors/effectors appear to heterodimerization. Glucocorticoids can interfere with organized determine the distinct features of ErbB1 down-stream signals. ErbB receptor dimerization in lung cells, leading to a switch from ErbB1 has a deletion mutant, EGFRvIII (also known as EGFR, ErbB1:ErbB4 to ErbB2:ErbB4 heterodimer expression (Table 1; type3 EGFR, de 2–7 EGFR, EGFR∗), which lacks extracellular Dammann et al., 2006). In addition to the signaling complex- domain of EGFR (Yamazaki et al., 1988). In addition, alter- ity and diversity of ErbB heterodimerization, the individual erbB native splicing and protein processing produce soluble EGFR genes or their products are subjected to alternative splicing or isoform (sEGFR). sEGFR lacks intracellular domain (Flickinger proteolytic processing, resulting in truncated isoforms lacking the et al., 1992; Rose-John and Heinrich, 1994; Perez-Torres et al., kinase domain or ligand-binding domain. These truncated iso- 2008). These truncated ErbB1 contribute to tumorigenesis, but forms function as an enhancer of tumorigenesis, a receptor decoy their role in brain is not fully understood (Baron et al., 2003; or a transcription factor (see below; Yamazaki et al., 1988; Lee Gan et al., 2009).

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Table 2 | Brain distribution and functions of ErbB1-4. cancer cells (Namba et al., 2006; Nagano et al., 2007). The differ- ences in the biological activities of EGF/ErbB1 signaling between ErbB receptor Tissue Cell type Function these two neuronal populations are presumably attributed to dif- ErbB1 Subventrucular Neural stem cell Proliferation/ ferences in the ErbB partner. The signal pathways of ErbB1:ErbB1 zone migration homodimers and ErbB1:ErbB4 heterodimers differ significantly Midbrain Dopaminergic Survival/ as discussed above. In addition to these neurons, astrocytes and neuron development their precursors express ErbB1, which is markedly enhanced Cortex, GABAergic Regulation of in response to injury-associated astrogliosis (Liu et al., 2006). hippocampus neuron synaptic function ErbB1 is also expressed in the pituitary and regulates the produc- Astrocyte Proliferation/ tion and release of cortisol and prolactin (Cooper et al., 2011; differentiation Dahlhoff et al., 2011). ErbB1 in the hypothalamus reacts with α Cerebellum Purkinje cell Development/ TGF , which is produced in the suprachiasmatic nucleus, and Granule cell proliferation regulates circadian rhythm (Kramer et al., 2001; Snodgrass-Belt Astrocyte et al., 2005). Pituitary grand Lactotroph Production/release of cortisol and ErbB2 (HER2, Neu) prolactin ErbB2 signals mainly link to the Ras-MAPK pathway and the PI3K-Akt pathway, leading to cell proliferation. Therefore, at ErbB2 Cerebellum, Oligodendrocyte Proliferation/ the postnatal stages, ErbB2 levels are limited to postmitotic cortex, Astrocyte differentiation neurons or glial cells (Abe et al., 2009a). There are a variety hippocampus, Radial glia of truncated ErbB2 isoforms that are produced by alternative midbrain, etc. splicing and metalloprotease digestion (Cappuzzo et al., 2012; ErbB3 Cortex, Oligodendrocyte Maturation/ Tse et al., 2012; Ward et al., 2012). p110ErbB2 (611CTF) and hippocampus, myelination p95ErbB2 (CTF648) both lack the extracellular domain and etc. contribute to cancer progression and metastasis (Xia et al., 2011; Ward et al., 2012), although their roles in the brain ErbB4 Cortex, GABAergic Attenuates are poorly understood. The carboxyl terminal of ErbB2 car- hippocampus, neuron synaptic function ries a PDZ-binding motif and associates with a leucine-rich Astrocyte Proliferation/ Oligodendrocyte differentiation molecule, Erbin (Huang et al., 2001). As Erbin attenuates the activation of Ras-MAPK signaling linked to cell proliferation, its Cerebellum Granule cell Regulation of interaction with ErbB2 is implicated in oligodendrocyte differ- synaptic function entiation and myelination (Tao et al., 2009; Dan et al., 2010; Midbrain Dopaminergic Survival, attenuates Liang et al., 2012). neuron synaptic function Proliferating neural stem cells or precursors express high levels of ErbB2 (Abe et al., 2009a) in addition to ErbB1. Oligodendrocyte precursors express ErbB2 together with ErbB3, In the central nervous system, ErbB1 protein levels are the and ErbB2 activation contributes to the proliferation and dif- highest during the gestational stages and gradually decline dur- ferentiation of these cells via ErbB3 phosphorylation (Flores ing development. Consistent with this expression pattern, neural et al., 2000). A recent study revealed that signals from stem cells in the subventricular zone (SVZ) are highly enriched ErbB2:ErbB3 complexes in the neocortex regulate the expres- with ErbB1 (Abe et al., 2009a). ErbB1 activation triggers the sion of disrupted schizophrenia 1 (DISC1), which has been proliferation and migration of neural stem cells and their imme- implicated in the genetics of schizophrenia (Seshadri et al., diate decedents (Aguirre et al., 2005, 2010). In addition to these 2010). In hippocampal neurons, ErbB2:ErbB4 heterodimers undifferentiated neural cells, several types of differentiated neu- influence the morphological differentiation of these cells rons also maintain expression at postnatal stages. In the mid- (Gerecke et al., 2004). brain region, the nigra-striatal dopamine neurons express ErbB1 together with ErbB4 (Abe et al., 2009a). ErbB1 activation con- ErbB3 (HER3) tributes to the survival and postnatal development of dopamin- ErbB3 displays ligand preference for some members of the NRG ergic neurons, although the molecular nature of the endogenous family; ErbB3 has a high affinity interaction with NRG1, NRG2, ErbB1 ligands has not been fully identified (Iwakura et al., 2005, and NRG6. Indeed, the intracellular domain of ErbB3 har- 2011; Namba et al., 2009). Various types of GABAergic neurons bors more tyrosine residues that accept various adaptor/effecter also carry ErbB1 receptors. Interneurons in the hippocampus molecules (Table 1). As its kinase activity is impaired, het- and neocortex as well as cerebella Purkinje cells express ErbB1 erodimer formation with ErbB2 or the other ErbBs is essential (Werner et al., 1988; Seroogy et al., 1995; Namba et al., 2006; to evoke signal transduction cascades. Alternative splicing of the Nagano et al., 2007; Abe et al., 2009b). In contrast to its action erbB3 gene produces soluble isoforms of ErbB3 (sErbB3) as well on dopaminergic neurons, the activation of ErbB1 in GABAergic as isoforms with truncations in the intracellular domain (Lee and neurons induces their de-differentiation, as seen in peripheral Maihle, 1998). Among these isoforms, p45 and p85 sErbB3s bind

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FIGURE 3 | Typical signal transduction from the ErbB4:ErbB1 and Erk(MAPK). (3) In the PI3K-Akt pathway, the activated ErbB dimer ErbB4:ErbB4 complex. Once ErbB1 is phosphorylated by the partner interacts with Grb2/Gab1 and forms complexes with activated PI3Kinase, ErbB, the following signal cascades are activated; (1) In the PLCγ-PKC leading to the conversion of PIP2 to PIP3 and Akt activation. (4) In the pathway, phosphorylated ErbB1 recruits and associates with PLCγ.Asa JAK-STAT pathway, ErbB kinase phosphorylates and induces JAK to bind result, PLCγ itself is phosphorylated to activate DAG/IP3 signaling (Chen to ErbB1. Activated JAK phosphorylates STAT and allows STAT to et al., 1996). (2) In the Ras-MAPK pathway, phosphorylated ErbB1 homodimerize and translocate into the nucleus. Once ErbB4 is associates with Shc and interacts with Grb2/Sos1. Activated Sos1 phosphorylated by ErbB4, the signaling cascades linked to differentiation triggers GDP/GTP exchange in Ras and activates Ras, driving the become activated, notably the PI3K-Akt pathway and the Ras-MAPK sequential kinase reactions of Raf(MAPKKK), MEK(MAPKK), and pathway with longer durations. to NRG and decrease the effective concentrations of NRG1 in the cycle cessation and differentiation (Muraoka-Cook et al., 2008; extracellular space (Lee et al., 2001; Lin et al., 2008). The trun- Ortega et al., 2012). In the erbB4 genome, alternative splicing of cated isoforms of ErbB3 are found in cortical astrocytes and might exon 15/16 and exon 26 produces ErbB4 variants, JM-a/b/c/d and be involved in attenuating NRG signaling (Citri and Yarden, 2006; CYT-1/2, respectively (Figure 4; Zeng et al., 2009; Veikkolainen Sharif and Prevot, 2010). et al., 2011). The phosphorylation of CYT-1 can recruit the In the brain, high ErbB3 expression is only found in oligo- p85 adaptor to activate PI3K-Akt signaling (Kainulainen et al., dendrocytes and their precursors. ErbB3 activation is involved in 2000). The CYT-1 sequence is susceptible to proteolytic cleav- their propagation and differentiation (Makinodan et al., 2012). age by TNF-alpha converting enzyme (TACE) and γ-secretase ErbB3 expression is also observed in neural precursor cells in (Vidal et al., 2005; Sundvall et al., 2010). Thus, ErbB4 proteol- the adult hippocampus and contributes to their proliferation, ysis produces an 80 kD intracellular fragment (ErbB4-ICD) and although ErbB3 expression is modest (Mahar et al., 2011). In liberates it into the cytoplasmic space. ErbB4-ICD interacts with human astrocytes, ErbB3, and ErbB1 form heterodimers that the transcription factor STAT5 and migrates into the nucleus as a transduce NRG-dependent signals (Sharif et al., 2009). Again, molecular chaperone (Vidal et al., 2005; Sundvall et al., 2010). EGF evokes NRG-like signaling through the dimerization of ErbB4 also contains a PDZ-binding motif at the carboxyl ter- ErbB3 and ErbB1. minal and is anchored to postsynaptic density protein 95 (PSD95) in neurons (Huang et al., 2000). Even when proteolytic cleav- ErbB4 (HER4) age produces ErbB4-ICD or when ErbB4 is phosphorylated with ErbB4 mainly links to the Ras-MAPK and PI3K-Akt pathways. the ErbB partner, the signal is only minimally transported to In contrast to ErbB1 signaling, ErbB4 phosphorylation induces the soma or translocated into the nucleus. Rather, the interac- sustained activation of the Ras-MAPK pathway, leading to cell tion with the scaffold protein PSD95 allows NMDA receptors to

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FIGURE 4 | Splice variants of ErbB4 proteins and their speciﬁc the nucleus with STAT and regulates gene transcription (A). The CYT-1 and signaling. The JM-a and JM-d isoforms of ErbB4 are cleaved by TACE or CYT-2 isoforms of ErbB4 differentially trigger Ras-MAPK signaling and/or γ-secretase and converted to ErbB4-ICD. ErbB4-ICD is translocated into PI3K-Akt signaling (B).

interact with ErbB4 and restrict ErbB4 signaling to the postsy- regulates the enzyme activity and expression of tyrosine hydrox- naptic compartments (Garcia et al., 2000). Accordingly, impaired ylase in vivo as well as dopamine synthesis and release (Kato NRG1/ErbB4 signal is thought to underlie NMDA receptor dys- et al., 2011). Although ErbB4 is suggested to contribute to the function found in brain diseases such as schizophrenia (Hahn migration and differentiation of immature GABAergic interneu- et al., 2006; Pitcher et al., 2011). ErbB4 also can form molecular rons, these processes also involve ErbB1, and thus, the interplay complexes with the receptor-type tyrosine phosphatase (Ptprz) between ErbB4 and ErbB1 needs to be characterized to reveal via its interaction with PSD95 (Fujikawa et al., 2007). In this the full mechanism (Mahar et al., 2011; Li et al., 2012). In complex, Ptprz interacts with ErbB4 as its substrate and de- our previous studies, these phenotypic actions of NRG1/ErbB4 phosphorylates ErbB4. Given the ligands for Ptprz (i.e., mid- signals appear to be more modest than those of EGF/ErbB1 kines and pleiotropins), NRG/ErbB4 signals can be disrupted by signals in neural cultures. Consistent with these ﬁndings, the other cytokines through this receptor-type tyrosine phosphatase gross brain structures and function of ErbB4-null knockout (Figure 5). mice appear to be modest compared with ErbB1-null knock- ErbB4 expression gradually increases in the brain and becomes out mice (Sibilia and Wagner, 1995; Sibilia et al., 1998; Thuret pronounced in postmitotic neurons such as GABAergic interneu- et al., 2004). In this context, the crucial functions and/or bio- rons, dopamine neurons, and cerebellar granule cells (Table 2; logical signiﬁcance of ErbB4 in the brain might not be fully Elenius et al., 1997; Abe et al., 2009a; Vullhorst et al., 2009). characterized. The developmental pattern of ErbB4 expression is the opposite of that of ErbB1 (Abe et al., 2009a). ErbB4 signals may accelerate IMPLICATIONS OF ABNORMAL ErbB SIGNALING IN BRAIN neural differentiation in these cell populations, potentially atten- DISEASES uating ErbB1 signaling (Woo et al., 2007; Fazzari et al., 2010). ErbB signaling contributes to the development and maintenance The NRG-driven up-regulation of glutamate receptor functions of various cell populations in the central nervous system and is may represent the typical phenotypic responses of this cell popu- therefore implicated in the etiology or neuropathology of vari- lation; ErbB4 activation regulates the activity and/or expression ous brain diseases such as schizophrenia and Parkinson’s disease, of both AMPA-type and NMDA-type glutamate receptors in which involve cell dysfunction of GABAergic and/or dopaminer- GABAergic neurons (Gajendran et al., 2009; Abe et al., 2011; gic neurons. Here we would like to discuss the potential patholog- Ting et al., 2011). ErbB4 in midbrain dopaminergic neurons ical links between ErbB signaling and these brain diseases.

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FIGURE 5 | Synaptic compartment of ErbB4 that binds to PSD95 activity and function (A). The PSD95-mediated interaction between or interacts with the phosphatase. The scaffolding protein PSD95 ErbB4 and a membrane attached phosphatase, Ptprz. Ptprz anchors ErbB4 and the NMDA receptor at postsynaptic sites. The eliminates the phosphate from ErbB4 and attenuates its molecular interaction between ErbB4 inﬂuences NMDA receptor signaling (B).

PARKINSON’S DISEASE leading to the loss of neurotrophic ErbB1 signals in this Parkinson’s disease is a progressive neurodegenerative disorder disease. in which patients exhibit obvious symptoms of motor dysfunction, such as shaking and muscle rigidity. This disease progresses SCHIZOPHRENIA to neurodegeneration of the midbrain dopaminergic neurons. ErbB1aswellasErbB4isdistributedinallthecellpopulations Consistent with the neurotrophic actions of EGF on this cell pop- that are implicated in schizophrenia neuropathology, includ- ulation, the protein levels of EGF and ErbB1 are diminished in ing GABAergic neurons, dopaminergic neurons, and glial cells. the postmortem brains of patients with this disease (Iwakura Several studies have focused on the ErbB1 molecule. Postmortem et al., 2005). A neurotrophic disturbance in ErbB1 signaling is studies revealed that the ErbB1 protein is up-regulated in the fore- reproduced in animal models of the disease; rats receiving a brain regions of schizophrenia patients (Futamura et al., 2002). dopaminergic neurotoxin exhibit decreased ErbB1 and dopamin- Animal studies demonstrate that acute and subchronic brain acti- ergic cell loss but EGF ameliorates these deficits (Pezzoli et al., vation of ErbB1 triggers dopamine release in the striatum or 1991; Ventrella, 1993; Iwakura et al., 2005). Similarly, the con- globus pallidus, leading to behavioral impairments relevant to tribution of ErbB4 signals to this illness is under investigation. schizophrenia (Futamura et al., 2003; Tohmi et al., 2005; Mizuno Because of the higher blood-brain permiability of type 1 NRG1 et al., 2008; Sotoyama et al., 2011). In contrast to the effects on (Kato et al., 2011), NRG1 was peripherally administeration to dopamine neurons, ErbB1 ligands negatively regulate GABAergic a Parkison’s disease model to induce the neuroprotection of development in the neocortex and attenuate the activity of glu- dopamine neurons (Zhang et al., 2004; Carlsson et al., 2011; tamate receptor channels in these neurons (Namba et al., 2006; Depboylu et al., 2012). Nagano et al., 2007). Conversely, quianozoline ErbB1 inhibitors The molecular neuropathology of Parkinson’s disease involves can ameliorate schizophrenia-related behaviors in various ani- not only ErbB1 but also ErbB-interacting molecules. For exam- mal models for schizophrenia (Mizuno et al., 2008). Both types ple, LINGO-1, which associates with the Nogo-receptors in the of model studies indicate a pathological link between ErbB1 nervous system, directly binds to ErbB1 to attenuate cell sur- hypersignaling and schizophrenia. Given that ErbB1 and ErbB4 vival signals (i.e., PI3K-Akt signaling) in dopamine neurons colocalization within the same neurons, it is likely that ErbB1 (Inoue et al., 2007). Consistent with this finding, LINGO-1 competes with NRG/ErbB4 signals, as was suggested in cancer expression is elevated in the substantia nigra of patients studies (Moghal and Sternberg, 1999; Pitfield et al., 2006; Das with Parkinson’s disease. The molecule parkin, which is the et al., 2010). causativegeneforinheritableParkinson’sdisease(Kitada et al., Genetic studies have also demonstrated that schizophrenia is 1998), maintains ErbB1 signaling under normal conditions. associated not only with the ligand NRG but also with its receptor Parkin can promote the ubiquitination and dissociation of ErbB4 (Stefansson et al., 2002). In 2006, SNP analysis revealed Eps15 from ErbB1 to attenuate the internalization and degra- a genetic association between the erbB4 gene and a particular dation of ErbB1 (Fallon et al., 2006). Conversely, mutations type of splicing pattern associated with this illness (Norton et al., in the parkin gene result in accelerated ErbB1 degradation, 2006; Silberberg et al., 2006). The risk of erbB4 SNPs appears

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to correlate with the disease-specific spicing pattern (i.e., JM-a Table 3 | Virokines that bind to ErbB receptors. and CYT-1) in the prefrontal cortex and hippocampus of patients Virokine (ErbB-binding proteins) Receptors Related (Law et al., 2007; Tan et al., 2010). A postmortem study also found proteins an increase in phosphorylated ErbB4 protein and its ability to form complexes with PSD95 but failed to detect a difference in VGF VGF ErbB1 EGF, TGFα total ErbB4 levels in schizophrenia patients (Hahn et al., 2006). (Vaccinia virus growth homodimer In addition to the neuropathology of GABAergic and factor, vaccinia 19kd dopaminergic neurons in schizophrenia, postmortem studies protein) indicate the deficits in white matter and myelin structures are CGF ErbB1 VGF associated with this illness (Davis et al., 2003; Flynn et al., 2003). (Cowpox growth factor) EGF family ErbB3 signals play crucial roles in oligodendrocyte myelination SPGF ErbB1 VGF and saltatory conduction of nerve impulses (Stewart and Davis, (Smallpox growth EGF family 2004). Thus, several schizophrenia studies have focused on ErbB3 factor) function. Aston et al. (2004) found that mRNA levels of genes SFGF ErbB1 containing VGF related to myelin and oligodendrocytes, including erbB3 mRNA, (Shope fibroma virus dimer EGF family are down-regulated in the middle temporal gyrus of schizophre- growth factor) nia patients (Aston et al., 2004). However, the genetic association MGF ErbB2/ErbB3 VGF between erbB3 SNPs and schizophrenia remains controversial (Myxoma virus growth EGF family (Kanazawa et al., 2007; Watanabe et al., 2007). In addition to factor) the genetic association between erbB SNPs and schizophrenia, E5 protein Human papilloma virus ErbB1 viral infection also directly triggers ErbB signaling and potentially type16 E5 protein ErbB4 (JM-b contributes to brain mal-development. CYT-1) IMPACT OF VIROKINES ON ErbB SIGNALING Human papillomavirus ErbB1, ErbB2 type6 E5 protein Virokine is a general term for a cytokine produced by viruses. By Bovine papillomavirus ErbB1 producing virokines, many viruses perturb the immune defense type1 E5 protein system of host organisms to escape clearance or promote host cell proliferation to enhance viral propagation (Klouche et al., 2004). A variety of virokines have been identified, including those that membrane-anchored molecule, like the EGF precursor, but lacks act on ErbB receptors (Table 3). In fact, some virokines are sug- the EGF-like domain. For example, the E5 protein of human gested to impair brain development (Billings et al., 2004). Thus, papillomavirus type 16(HPV-16) associates with the ATPase virokine production following viral infection directly influences motif of the ErbB1 tyrosine kinase domain, attenuate its inter- brain development and might support the schizophrenia hypoth- action with Cbl, and inhibits the internalization and degrada- esis of viral infection (Waddington and Buckley, 1996; Brown and tion of ErbB1 (Figure 6). Accordingly, papillomavirus infection Derkits, 2010). enhances EGF/ErbB1 signaling to promote host cell prolifera- Vaccinia virus growth factor (VGF, Vaccinia virus 19- tion (Chang et al., 2001; Venuti et al., 2011; Ganguly, 2012). kilodalton protein) is encoded by the genome of vaccinia virus In addition to ErbB1, the E5 protein also binds to the JM- inthepoxvirusfamilyandhasanaminoacidsequencehomol- b/CYT-1 isoform of ErbB4 and promotes host cell survival ogous to EGF (Figure 6). VGF is produced and secreted from (Chen et al., 2007). The E5 protein in other papillomaviruses its membrane-anchored precursor and binds to ErbB1 receptors. (human papillomavirus type 6 and bovine papillomavirus type1) VGF activates the Ras-MAPK pathway of host cells and pro- exerts similar modifications on ErbB signaling (Martin et al., motes cell proliferation (Eppstein et al., 1985; Twardzik et al., 1989; Cohen et al., 1993; Conrad et al., 1994). It is noteworthy 1985). Cowpox virus growth factor (CGF) displays high homol- that the human uterus can be infected with human papillo- ogy to VGF and enhances host cell propagation (da Fonseca et al., mavirus type 16. Assuming that a human embryo develops in a 1999). Additional EGF-like virokines have been identified in other uterus harboring papillomavirus, the potential direct or indirect pox viruses, including smallpox virus growth factor (SPGF; Kim impact of the E5 protein on fetal brain development cannot be et al., 2004), myxoma virus growth factor (MGF; Opgenorth overlooked. et al., 1993), and shope fibroma virus growth factor (SFGF; Chang et al., 1987; Ye et al., 1988). These virokines also carry an EGF- PROVISIONAL CONCLUSION like sequence and interact with ErbB receptors. According to the Studies in cancer biology clearly indicate the pathologic powers schizophrenia hypothesis of maternal and perinatal viral infec- of abnormal ErbB signaling and its contribution to oncogenesis, tion, the infection of these viruses and their translocation to asthma, injury repair, and rheumatoid arthritis (Stoll and Elder, the brain may perturb the normal development of dopamin- 1998; Davies et al., 1999; Satoh et al., 2001; Bersell et al., 2009; ergic or GABAergic neurons, although this assumption is fully Calvo et al., 2010; Finigan et al., 2011; Yarden and Pines, 2012). hypothetical. In contrast to our knowledge of ErbB signaling in the periphery, In addition to soluble virokines, virus-derived effectors can the biological functions and regulation of ErbB signaling in the affect intracellular ErbB signaling. E5 is one of the early gene brain are still limited (Buonanno and Fischbach, 2001; Wong and products of human papillomaviruses. E5 protein is also a Guillaud, 2004; Mei and Xiong, 2008). The ligand-bound ErbB

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FIGURE 6 | Primary sequences of ErbB-interacting virokines and adaptor, E5, which is produced by papillomaviruses, associates receptor interactions. The primary amino acid sequences of EGF with the kinase domain of ErbB and inhibits its internalization and virokines in the poxvirus family are shown (A).AnErbB and/or degradation (B). receptor does not transmit signals, and instead the ErbB partner (Kinugasa et al., 2004; Nakanishi et al., 2006; Oyagi et al., 2009, acts as a kinase substrate to trigger intracellular signaling. In addi- 2011). Together with the proteolytic regulation of ErbB proteins tion, we need to consider which individual ErbB splicing isoforms and ligand precursors, ErbB signaling is regulated at multiple lev- are expressed in individual neural cells because some ErbB iso- els, including SNPs, alternative splicing, proteolytic processing, forms have a dominant-active or -negative function. Currently, intracellular translocation, and signal cross talks between ErbBs. we only know that erbB gene products are present in certain We hope this review will hint at the biological importance of ErbB neurons or glia and not the real structures of particular ErbB iso- in the nervous system and drive readers to challenge biological or forms in various brain regions. In this context, a more elaborate pathological questions regarding ErbB signaling. analysis may be required to accurately discuss their functions in the nervous system. ACKNOWLEDGMENTS Although there are a total of four ErbB molecules, their lig- The authors are grateful to N. Takei for comments and ands have signiﬁcantly more diversity. There are six endogenous suggestions. The experimental results obtained by the ErbB ligands in the EGF family and six in the NRG family. Virus- authors were, in part, supported by JSPS KAKENHI (Yuriko derived ErbB ligands also need to be considered. In contrast to Iwakura; No.24700375), MEXT KAKENHI (Hiroyuki Nawa; the investigations on EGF or NRG1, the contribution of the other No.24116010), JSPS KAKENHI (Hiroyuki Nawa; No.22300107), ligands, such as HB-EGF and NRG6 (neuroglycan C), is poorly The Naito Foundation (Yuriko Iwakura), and a grant for understood even though those are highly expressed in the brain Promotion of Niigata University Research Projects.

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