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Home , ErbB, Neuregulin 3, Receptor tyrosine kinase

Endocrine-Related (2001) 8 151–159

The ErbB family as signal integrators

N E Hynes, K Horsch, M A Olayioye and A Badache

Friedrich Miescher Institute, PO Box 2543, CH-4002 Basel, Switzerland (Requests for offprints should be addressed to N E Hynes, Friedrich Miescher Institute, R-1066.206, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. Email: [email protected]) (M A Olayioye is now at The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria 3050, Australia)

Abstract ErbB receptor tyrosine (RTKs) and their ligands have important roles in normal development and in human cancer. Among the ErbB receptors only ErbB2 has no direct ; however, ErbB2 acts as a co-receptor for the other family members, promoting high affinity ligand binding and enhancement of ligand-induced biological responses. These characteristics demonstrate the central role of ErbB2 in the receptor family, which likely explains why it is involved in the development of many human malignancies, including breast cancer. ErbB RTKs also function as signal integrators, cross-regulating different classes of membrane receptors including receptors of the family. Cross-regulation of ErbB RTKs and receptors represents another mechanism for controlling and enhancing tumor cell proliferation. Endocrine-Related Cancer (2001) 8 151–159

Introduction The EGF-related peptide growth factors The epidermal (EGF) or ErbB family of type ErbB receptors are activated by ligands, known as the I receptor tyrosine kinases (RTKs) has four members:EGF EGF-related peptide growth factors (reviewed in Peles & receptor, also termed ErbB1/HER1, ErbB2/Neu/HER2, Yarden 1993, Riese & Stern 1998). There are numerous ErbB3/HER3 and ErbB4/HER4. We will refer to them, ErbB-specific ligands, summarized in Fig. 1, each with an henceforth, as the ErbB receptors. All family members have EGF-like domain which is sufficient to confer binding in common an extracellular ligand-binding domain, a single specificity. These include EGF, (AR) and membrane-spanning region and a cytoplasmic transforming growth factor-α (TGFα), which bind tyrosine domain. A family of ligands, the EGF-related specifically to ErbB1, and (BTC), peptide growth factors, bind the extracellular domain of ErbB heparin-binding EGF (HB-EGF) and (EPR), receptors leading to the formation of receptor homo- and which exhibit dual specificity in that they bind both ErbB1 heterodimers. Dimerization consequently stimulates the and ErbB4. The (NRG) comprise the third ligand intrinsic activity of the receptors and triggers family. NRG-1 and NRG-2 (Chang et al. 1997) both bind autophosphorylation/transphosphorylation of specific ErbB3 and ErbB4, whereas NRG-3 (Zhang et al. 1997) and tyrosine residues within the cytoplasmic domain. These NRG-4 (Harari et al. 1999) bind ErbB4 but not ErbB3. phosphorylated residues serve as docking sites for signaling Despite the abundance of ligands identified for these three molecules involved in the regulation of intracellular signaling ErbB receptors, no direct ligand for ErbB2 has yet been cascades. Ultimately, downstream effects on expression discovered. However, increasing evidence suggests that the determine the biological response to receptor activation. primary function of ErbB2 is as a co-receptor. ErbB receptors are expressed in a variety of tissues of epithelial, mesenchymal and neuronal origin where they play fundamental roles in development, proliferation and ErbB2 plays a central role in the ErbB differentiation. Moreover, deregulated expression of ErbB family of receptors receptors, in particular ErbB1 and ErbB2, has been implicated in the malignancy of numerous types of human Binding of the EGF-related peptide growth factors to their tumors, including breast cancer. respective receptor induces receptor dimers and heterodimers.

Endocrine-Related Cancer (2001) 8 151–159 Online version via http://www.endocrinology.org 1351-0088/01/008–151  2001 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 10:41:20AM via free access Hynes et al.: ErbB receptor signaling network

Figure 1 Binding specificities of the EGF-related peptide growth factors. There are four categories of ligands that bind ErbB family receptors. EGF, AR and TGFα bind ErbB1; BTC, HB-EGF and EPR bind ErbB1 and ErbB4; NRG-1 and NRG-2 bind ErbB3 and ErbB4; NRG-3 and NRG-4 bind ErbB4.

Heterodimerization is accomplished by the bivalent nature of ErbB signaling potential. The subsets of phosphotyrosine- the ligands (Groenen et al. 1994, Lemmon et al. 1997, Tzahar binding signaling molecules (referred to as SH2- and et al. 1997), which allows high affinity binding to a primary PTB-binding ) recruited to an activated receptor are receptor and recruitment of the second partner. Importantly, defined by the pattern of phosphorylated tyrosine residues in the second partner is preferentially ErbB2 (Graus-Porta et al. the C-terminus of each receptor. We speculated that signal 1997, Tzahar et al. 1997), which acts as a co-receptor diversification arises at one level by differential increasing the affinity of ligand binding to the dimeric receptor transphosphorylation of a given receptor in a distinct ErbB complex (Karunagaran et al. 1996, Jones et al. 1999). dimer. In order to approach this experimentally, NIH3T3 In order to explore the role of ErbB2 in more detail, fibroblasts expressing defined combinations of ErbB we have down-regulated its function using an intracellularly receptors have been developed and used to examine the expressed ErbB2–specific single chain or Fv ability of an individual ErbB receptor to couple to specific domain (scFv5R). Targeting of scFv5R to the endoplasmic signaling molecules in the context of distinct receptor dimers. reticulum causes retention of ErbB2 in this compartment More specifically, ErbB1 signaling was examined after leading to loss of receptor function (Beerli et al. 1994). This activation either by EGF in the context of ErbB1 approach has yielded valuable information, revealing the homodimers or by NRG-1 in the context of a ErbB1/ErbB4 central role of ErbB2 in this receptor family. Our results heterodimer (Fig. 2). In both cases ErbB1 coupled to the show that ErbB2 plays an important function in the adaptor protein Shc, but only when activated by EGF was it potentiation of ligand-induced intracellular signaling (Beerli able to interact with Grb2 and Cbl. Compared with the rapid et al. 1995, Graus-Porta et al. 1995) and biological activity internalization of EGF-activated ErbB1, NRG-1-activated (Spencer et al. 2000), characteristics of ErbB2 which provide ErbB1 showed delayed internalization characteristics an explanation for its high oncogenic potential. (Olayioye et al. 1998). Tryptic phosphopeptide analyses ErbB receptors acquire distinct signaling clearly showed that there are ligand-dependent differences in properties dependent upon their the patterns of ErbB1 (Olayioye et al. 1998) which could provide a biochemical explanation for the dimerization partner observed differences in recruitment of Grb2 and Cbl. The ability of ErbB ligands to induce not only receptor Interestingly, Cbl has recently been identified as a RING homodimers but also heterodimers expands and diversifies finger domain-containing E3 ubiquitin protein which

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Figure 2 Signaling properties of ErbB1 activated in an ErbB1 homodimer by EGF compared with ErbB1 transactivated by NRG-1 in an ErbB1/ErbB4 heterodimer. P, phosphotyrosine. is required for ErbB1 ubiquitylation and targeting of the Mice individually null for ErbB2, ErbB4 and NRG-1 each receptor to the lysosomal compartment (Levkowitz et al. demonstate a lack of trabeculae formation in the 1999). Thus, the difference in internalization kinetics (Gassmann et al. 1995, Lee et al. 1995, Meyer & Birchmeier observed for EGF- compared with NRG-1-activated ErbB1 1995), showing that an important signaling moiety in the might be explained by Cbl binding to the former but not to myocardium is the ErbB2/ErbB4 heterodimer stimulated in a the latter. Our results show that the coupling of a given paracrine fashion by NRG-1. The essential contribution of receptor to specific intracellular signaling proteins is this receptor collaboration to heart development is clearly modulated by the dimerization partner and may indeed observed in ErbB2 null mice, where NRG-1-induced ErbB4 originate from differential receptor phosphorylation. dimers cannot replace the function of the ErbB2/ErbB4 heterodimer. Receptor heterodimers enhance and Using fibroblasts expressing defined combinations of ErbB proteins, we have examined the ability of distinct diversify the signal potential of the ErbB receptor dimers to induce various network pathways (Olayioye et al. 1999). Importantly, as implied The ErbB family has evolved from a single ligand/receptor from the phenotype of the knock-out mice, our results combination in Caenorhabdites elegans (Aroian et al. 1990), showed directly that a heterodimer can acquire novel through Drosophila with one receptor and four ligands signaling properties that are not the sum of the activity of (Wasserman & Freeman 1997), to vertebrates where four individual receptor dimers. Cells in which ErbB2 was ErbB receptors bind multiple EGF-related ligands (reviewed activated by a dimerization inducing ErbB2 specific in Stein & Staros 2000). Consequently, numerous ErbB monoclonal (mAb) were compared with cells homo- and heterodimer combinations are possible in where ErbB4 dimers or ErbB2/ErbB4 heterodimers were vertebrates, suggesting that the ErbB receptor family has activated by NRG-1. Each of these ErbB dimers induced evolved to provide a high degree of signaling diversity, elevated intracellular MAP kinase activity. In striking which may have been necessary for the evolutionary contrast, only the ErbB2/ErbB4 heterodimers stimulated development of metazoans. activation of Stat5, a member of the signal transducer and Phenotypes of ErbB receptor knock-out mice are the activator of transcription (Stat) family (Fig. 3) (Olayioye et most striking proof of the power of receptor heterodimers. al. 1999). It will be interesting to explore the role of Stat5 www.endocrinology.org Downloaded from Bioscientifica.com153 at 09/28/2021 10:41:20AM via free access Hynes et al.: ErbB receptor signaling network

Figure 3 An ErbB heterodimer is capable of acquiring novel signaling properties. ErbB2 homodimers were induced by mAb binding; ErbB2/ErbB4 heterodimers and ErbB4 homodimers were induced by NRG binding. All three ligand dimers activated the MAP kinase (MAPK) pathway; however, only ErbB2/ErbB4 heterodimers activate Stat5. P, phosphotyrosine. downstream of the ErbB2/ErbB4 heterodimer considering the receptors (GPCR), whose agonists stimulate MAP kinase via importance of this dimer in heart development. transactivation of ErbB1. For more detailed discussion of this cross-talk the interested reader is referred to some recent The ErbB receptors and human cancer reviews (Carpenter 1999, Hackel et al. 1999, Luttrell et al. 1999). Cross-regulation between ErbB receptors and Deregulated expression of ErbB receptors, in particular members of the family has also been ErbB1 and ErbB2, has been implicated in the development observed. Cytokine receptors are devoid of kinase activity and malignancy of numerous types of human . The and associate wth members of the Janus tyrosine kinase (Jak) interested reader is referred to these reviews (Hynes & Stern family to transduce signals. This cross-regulation results in 1994, Salomon et al. 1995, Tang & Lippman 1998). either a positive or a negative influence on the target Overexpression of ErbB2 is observed in a significant receptor. As an example of positive regulation, activation of proportion of breast and ovarian cancers, where it is the growth (GH) receptor induces the MAP kinase associated with poor prognosis (Slamon et al. 1989). pathway through ErbB1. More specifically, GH activates Overexpression of ErbB2 triggers ligand-independent Jak2 which phosphorylates a tyrosine residue in the activation of the kinase domain, apparently as a result of cytoplasmic domain of the ErbB1 leading to Grb2 association spontaneous dimer formation. Furthermore, many breast and stimulation of the MAP kinase pathway (Yamauchi et tumors display autocrine activation of ErbB1 due to al. 1997). expression of one or more ErbB1 ligands (Salomon et al. 1995). The ability of ErbB2 to potentiate ErbB1 signaling, as discussed above, very likely leads to an enhancment of Cross-regulation of ErbB receptors and the malignant process. cytokine receptors in mammary gland development and breast cancer ErbB receptors as signal integrators Receptor tyrosine kinases and cytokine receptors have also An emerging theme in the signal transduction area is been shown to negatively regulate each other. If we consider cross-regulation of different classes of membrane receptors; the mammary gland specifically, there is a complex ErbB RTKs are prime examples of signal integrators. This interaction between ErbB1 and prolactin (Prl) receptor (Fig. has been particularly well studied for the G-protein coupled 4). On the one hand, Prl receptor activation has a negative

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Figure 4 Cross regulation of ErbB1 and Prl receptor in mammary cells. Prl receptor activation stimulates a Ser/Thr (S/T) kinase which phosphorylates ErbB1 leading to down-regulation of its signaling potential (upper panel). ErbB1 activation induces expression of a PTP which inhibits Prl-induced Jak2 activation (lower panel). P, phosphotyrosine. influence on ErbB1-induced signaling. In mammary cells Sheffield 1998). Conversely, it has been known for a number continuously exposed to Prl, ErbB1 was found to be of years that EGF has a negative effect upon Prl receptor phosphorylated on specific residues, a modification signaling (Hynes et al. 1990, Marte et al. 1995). Very which had a negative effect upon its kinase activity leading recently, we have found that continuous exposure of to impaired EGF-induced biological responses (Quijane & mammary cells to EGF dampens the ability of the cells to www.endocrinology.org Downloaded from Bioscientifica.com155 at 09/28/2021 10:41:20AM via free access Hynes et al.: ErbB receptor signaling network respond to Prl-induced signaling, due to EGF stimulation of activation of Jak2 led to an enhancement of ErbB2 tyrosine a protein tyrosine (PTP) which negatively phosphorylation. Moreover, blocking autocrine production regulates the Prl receptor-associated Jak2 kinase (K Horsch, of Prl in these tumor cells led to a decrease in the M Schaller & N E Hynes, unpublished results). phosphotyrosine content of ErbB2 and a decrease in MAP It is interesting to consider the negative regulation kinase activity (Yamauchi et al. 2000). Intriguingly, an mediated by Prl receptor on ErbB1 and vice versa in light of examination of approximately 70 primary breast tumors their roles in the development of the mammary gland. ErbB1 revealed that the vast majority co-expressed Prl and its is expressed at all stages (Schroeder & Lee 1998, Darcy et receptor, and of these the ErbB2 overexpressing sub-group al. 2000) and appears to have a particularly important role in had the highest proliferative activity (Yamauchi et al. proliferation of ductal epithelial cells since wa-2 mice, which 2000). Both Prl receptor (Brisken et al. 1999) and ErbB2 harbor a mutation in the ErbB1 kinase domain, exhibit sparse (Jones & Stern 1999) play important roles during normal ductal growth (Fowler et al. 1995). Prl receptor does not development of the mammary gland. It will be interesting appear to have a major role in the proliferative phase, but to examine whether they biologically synergize during plays an essential role in differentiation of the gland into a breast tumor development. milk producing organ (Brisken et al. 1999). ErbB1 negative regulation of Prl signaling might reflect a general mechanism ErbB1 cooperates with -6 (IL-6) to prevent differentiation-inducing signals during the normal in breast cancer cells proliferative stage of development. Conversely, it is not suprising that ErbB1, a major growth promoter, is IL-6 is a member of the IL-6-type cytokine family which down-regulated during differentiation. Moreover, a loss of comprises oncostatin M, leukemia inhibitory factor, ciliary this mechanism might even play a role in tumor neurotropic factor and IL-11. These peptides promote similar development. biological responses in various tissues and cells. This ErbB2 and Prl receptor cross-regulation has also been redundancy in biological actions can be explained at the observed. It was recently shown in an ErbB2 molecular level because the different members of this cytokine overexpressing breast tumor cell line that Prl-mediated family share signaling molecules. Indeed, IL-6-type cytokines

Figure 5 Cooperation between IL-6 receptor and ErbB1 in T47D breast cancer cells. ErbB1 is activated to low levels due to autocrine stimulation, providing a scaffold for signaling molecules such as Grb2, Gab1 and Shp-2. Following IL-6 stimulation, Jak1 is activated leading to the recruitment and phosphorylation of Shp-2 and Gab1 which, in turn, recruit signaling molecules which feed into the MAP kinase (MAPK) pathway. P, phosphotyrosine.

156 Downloadedwww.endocrinology.org from Bioscientifica.com at 09/28/2021 10:41:20AM via free access Endocrine-Related Cancer (2001) 8 151–159 bind to multimeric receptors comprising an α chain which Acknowledgements confers ligand specificity and a signal transducing β subunit, The work in this laboratory is supported by the Novartis gp130, which is common to all IL-6-type cytokines (Heinrich Research Foundation. A B was supported in part by a et al. 1998, Hirano 1998). IL-6-type cytokines have diverse grant from the Gertrud Hagmann-Stiftung fuer actions on breast cancer cells, including changes in Malignomforschung and the Swiss Cancer League. morphology, decreased cell–cell association and inhibition of proliferation (Tamm et al. 1989, Douglas et al. 1997, Badache & Hynes 2001). IL-6 and other family members are References expressed in many primary breast tumors (Crichton et al. 1996, Aroian RV, Koga M, Mendel JE, OhshimaY & Sternberg PW Robinson et al. 1998, Fontanini et al. 1999). Intriguingly, IL-6 1990 The let-23 gene necessary for Caenorhabditis elegans expression is reduced in invasive breast carcinoma relative to vulval induction encodes a tyrosine kinase of the EGF receptor normal mammary tissue and its expression level appears to be family. Nature 348 693–699. inversely associated with histological grade (Basolo et al. Badache A & Hynes NE 2001 inhibits proliferation 1996, Fontanini et al. 1999). Although little is known about and, in cooperation with an epidermal IL-6-induced signal transduction in breast cancer, these autoctrine loop, increases migration of T47D breast cancer cells. observations suggest that this cytokine might be involved in Cancer Research 61 383–391. 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