Regular article
ErbB-4: mechanism of action and biology

https://doi.org/10.1016/S0014-4827(02)00100-3Get rights and content

Abstract

The most recently described member of the ErbB receptor tyrosine kinase family is ErbB-4. In general, the structure of this receptor and its mechanism of action is similar to that described for ErbB-1. However, significantly less is known about ErbB-4 and there are several novel aspects to its structure, mechanism of action, and biology. This includes the spectrum of ligands that activate ErbB-4, the presence of functionally distinct isoforms, a proteolytic processing pathway to the nucleus, and the capacity to induce a spectrum of cellular responses such as mitogenesis, differentiation, growth inhibition, and survival.

Section snippets

Introduction: receptor identification, structure, isoforms, and gene localization

Employing a strategy of homology cloning, ErbB-4 was cloned from a human mammary carcinoma cell line and its cDNA sequence determined [1]. That data showed ErbB-4 to be related in sequence to other ErbB receptors and to be organized in a similar fashion (Fig. 1). A single transmembrane domain separates equal sized ecto- and cytoplasmic domains. Within the ectodomain is a cleaved signal sequence and two cysteine-rich regions (domains II and IV), typical of ErbB receptors; nearly all of the 50

Receptor ligands

Ligands, which bind to ErbB-4 with high affinity and specificity and which provoke receptor activation and signaling, are divided into two groups, i.e., the neuregulins, also termed heregulins, and certain members of the epidermal growth factor (EGF) family of ErbB-1 ligands (Fig. 2). For consistency, the term neuregulin is used exclusively in this review. There are four neuregulin genes, denoted 1, 2, 3, and 4, and the product of each is capable of recognizing ErbB-4 in a biologically

Receptor activation and signaling

Following ligand binding, the ErbB-4 receptor is activated by a process common to other ErbB receptors, i.e., dimerization and autophosphorylation (Fig. 2). Initial studies showed that, unlike ErbB-3, ligand binding provoked autophosphorylation of ErbB-4 in a cellular environment devoid of other ErbB receptors [1], [6], [17]. In this regard ErbB-4 is analogous to ErbB-1. However, numerous studies have reported that heterodimerization of ErbB-4 with ErbB-2 forms a higher affinity binding site,

Receptor trafficking

While ErbB-1 and most growth factor receptor tyrosine kinases are rapidly internalized through clathrin-coated pits following ligand binding, ErbB-4 is internalized very slowly after addition of its ligand [41]. That some ligand:ErbB-4 complexes are, in fact, sorted to lysosomes is indicated by the appearance of low molecular weight degradation products of the ligand [42]. ErbB-4 internalization is sufficiently slow that mechanisms other than the clathrin-coated pit need to be considered.

The

Growth responses in experimental systems

Numerous articles have reported the influence of neuregulin/heregulin on the growth of cell lines that endogenously express ErbB-4. However, in nearly all of these cell lines ErbB-3 is also expressed and hence it is difficult to discern whether the cell response is mediated by ErbB-3 or ErbB-4 or both. For this reason these articles are not reviewed herein. Investigators have employed a few cell systems to experimentally evaluate growth responses mediated directly by ErbB-4 and in some cases by

Roles in normal and tumor tissues

A survey of ErbB receptor expression in a large number of adult and fetal human tissues showed that ErbB-4 is ubiquitously expressed [72]. Expression is highest in brain and heart, but significant levels are present in the epithelia of skin, gastrointestinal, urinary, reproductive, and respiratory tracts, along with skeletal muscle, circulatory, endocrine, and nervous systems. Also, a variety of human cancers express ErbB-4, although squamous carcinomas seem relatively devoid of this receptor.

Mammary tissue

Three studies have examined ErbB-4 expression in normal mammary tissue by western blotting [73] or immunohistochemistry [72], [74]. The studies argue that ErbB-4 is highest during pregnancy and occurs primarily in the ductal epithelium, especially at the terminal ducts or end buds. Expression at lower levels is detected in nulliparous animals and during lactation and involution. Using polymerase chain reaction analysis, expression of mRNA for both the CYT-1 and CYT-2 isoforms of ErbB-4 have

Other tumors

ErbB-4 expression has been noted in several other tumors in addition to mammary carcinoma [53], [79], [84], [85], [86], [87], [88], [89], [90]. These include carcinomas of the colon, prostate, lung, ovary, pancreas, endometrium, bronchus, cervix, stomach, and thyroid. Also, some astrocytomas and soft tissue sarcomas are reported to express ErbB-4. Expression of all known ErbB-4 isoforms (Jm-a, Jm-b, CYT-1, and CYT-2) have been tested in ovarian tumor specimens [90]. The Jm-a, CYT-1, and CYT-2

Heart development

The initial cloning studies of ErbB-4 also made clear that expression of this receptor was very high in the heart, skeletal muscle, and brain. Targeted disruption of the ErbB-4 gene in mice produces, in nullizygous animals, an embryonic lethal phenotype at approximately E10.5 [95]. In the embryonic heart, ErbB-4 is highly expressed in both the atrial and ventricular myocardium (muscle tissue), but is not detectable in the endocardium or epithelial lining. In the heart of ErbB-4 −/− embryos,

Nervous system

ErbB-4 expression is widespread in various parts of the brain and nervous system [95], [99], [100], [101], [102], [103], including the olfactory bulb [103], [104], [105] and retina [106]. This is reflected in the phenotype of knockout mice [95]. While the ErbB-4 −/− mice die at embryonic day 10.5 due to abnormal development of the heart, axonal guidance is also impaired. In contrast to the cardiac defect, which is shared by mice nullizygous for ErbB-2 or neuregulin, misinervation of axons in

Miscellaneous systems

Understanding of the role of ErbB-4 in other tissues is only beginning, but given its widespread distribution in embryonic and adult tissues, functions in additional systems will not be surprising. These investigations include the role of ErbB-4 in hypothalamus and reproductive behavior [122], palatogenesis and its disorders [123], tooth development [124], chondrocyte biology [125], and pancreatic islet development [126], [127]. Finally, two reports identify ErbB-4 on the outer surface of the

Concluding remarks

The author regrets that space limitation requires the omission of many studies indirectly related to the focus of this review and apologizes for the failure to cite any publication directly related to ErbB-4 function and biology. The interested reader is referred to other reviews for additional information and references. Many of these can be found in this issue of this journal. Other review articles and their focus are as follows: ErbB-4 [128], ErbB receptors [129], [130], [131], [132], ErbB-4

Acknowledgements

The author appreciates the efforts of Sue Carpenter in manuscript preparation and Lori Bennett in preparation of figures. Support of National Cancer Institute grant CA97456 is appreciated.

References (152)

  • J.T. Jones et al.

    Binding specificities and affinities of egf domains for ErbB receptors

    FEBS Lett.

    (1999)
  • K. Feroz et al.

    ErbB2 and ErbB3 do not quantitatively modulate ligand-induced ErbB4 tyrosine kinase phosphorylation

    Cell. Signal.

    (2002)
  • J.M. Mendrola et al.

    The single transmembrane domains of ErbB receptors sel-associate in cell membranes

    J. Biol. Chem.

    (2002)
  • J.-M. Culouscou et al.

    HER4 receptor activation and phosphorylation of Shc proteins by recombinant heregulin-Fc fusion proteins

    J. Biol. Chem.

    (1995)
  • J. Baulida et al.

    All erbB receptors other that the epidermal growth factor receptor are endocytosis impaired

    J. Biol. Chem.

    (1996)
  • J. Baulida et al.

    Heregulin degradation in the absence of rapid receptor-mediated internalization

    Exp. Cell Res.

    (1997)
  • M. Vecchi et al.

    Selective cleavage of the heregulin receptor ErbB-4 by protein kinase C activation

    J. Biol. Chem.

    (1996)
  • W. Zhou et al.

    Heregulin-dependent trafficking and cleavage or ErbB-4

    J. Biol. Chem.

    (2000)
  • C. Rio et al.

    Tumor necrosis factor-α-converting enzyme is required for cleavage of erbB4/HER4

    J. Biol. Chem.

    (2000)
  • Y.Z. Huang et al.

    Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses

    Neuron

    (2000)
  • Y.Z. Huang et al.

    Compartmentalized NRG signaling and PDZ domain-containing proteins in synapse structure and function

    Int. J. Dev. Neurosci.

    (2002)
  • M. Zhang et al.

    Expression of heregulin and ErbB/Her receptors in adult chinchilla cochlear and vestibular sensory epithelium

    Hearing Res.

    (2002)
  • J.A. Schroeder et al.

    Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland

    J. Biol. Chem.

    (2001)
  • V. Kainulainen et al.

    A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis

    J. Biol. Chem.

    (2000)
  • B.D. Cohen et al.

    HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers

    J. Biol. Chem.

    (1996)
  • B.D. Cohen et al.

    The relationship between human epidermal growth-like factor receptor expression and cellular transformation in NIH3T3 cells

    J. Biol. Chem.

    (1996)
  • S. Erlich et al.

    ErbB-4 activation inhibits apoptosis in PC12 cells

    Neuroscience

    (2001)
  • Y. Goldshmit et al.

    Neuregulin rescues PC12-ErbB4 cells from cell death induced by H2O2

    J. Biol. Chem.

    (2001)
  • U. Vogt et al.

    Amplification of erbB-4 oncogene occurs less frequently than that of erbB-2 in primary human breast cancer

    Gene

    (1998)
  • O. Merimsky et al.

    ErbB-4 expression in limb soft-tissue sarcomacorrelation with the results of neoadjuvant chemotherapy

    Eur. J. Cancer

    (2002)
  • O. Merimsky et al.

    Correlation between c-erbB-4 receptor expression and response to gemcitabine-cisplatin chemotherapy in non-small-cell lung cancer

    Ann. Oncol.

    (2001)
  • Y.-Y. Zhao et al.

    Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes

    J. Biol. Chem.

    (1998)
  • H. Steiner et al.

    Differential expression of ErbB3 and ErbB4 neuregulin receptors in dopamine neurons and forebrain areas of the adult rat

    Exp. Neurol.

    (1999)
  • G.D. Plowman et al.

    Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family

    Proc. Natl. Acad. Sci. USA

    (1992)
  • D.B. Zimonjic et al.

    Localization of the human HER4/erbB-4 gene to chromosome 2

    Oncogene

    (1995)
  • K. Elenius et al.

    Characterization of a naturally occurring ErbB-4 isoform that does not bind or activate phosphatidyl inositol 3-kinase

    Oncogene

    (1999)
  • T.T. Junttila et al.

    ErbB4 and its isoforms. Selective regulation of growth factor responses by naturally occurring receptor variants

    Trends Cardiovasc. Med.

    (2000)
  • G.D. Plowman et al.

    Heregulin induces tyrosine phosphorylation of HER4/p180erbB4

    Nature

    (1993)
  • H. Chang et al.

    Ligands for ErbB-family receptors encoded by a neuregulin-like gene

    Nature

    (1997)
  • K.L. Carraway et al.

    Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases

    Nature

    (1997)
  • D. Zhang et al.

    Neuregulin-3 (NRG3)a novel neural tissue-enriched protein that binds and activates ErbB4

    Proc. Natl. Acad. Sci. USA

    (1997)
  • D. Harari et al.

    Neuregulin-4a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase

    Oncogene

    (1999)
  • S.S. Hobbs, S.L. Coffing, A.T.D. Le, E.M. Cameron, E.E. Williams, M. Andrew, E.N. Blommel, R.P. Hammer, H. Chang, D.J....
  • D.J. Riese et al.

    Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-β

    Oncogene

    (1996)
  • K. Elenius et al.

    Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation

    EMBO J.

    (1997)
  • T. Komurasaki et al.

    Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3, and ErbB-4

    Oncogene

    (1997)
  • S.J. Busfield et al.

    Characterization of a neuregulin-related gene, Don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus

    Mol. Cell. Biol.

    (1997)
  • S. Higashiyama et al.

    A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4

    J. Biochem.

    (1997)
  • D.J. Riese et al.

    The cellular response to neuregulins is governed by complex interactions of the erbB receptor family

    Mol. Cell. Biol.

    (1995)
  • R.R. Beerli et al.

    Neu differentiation factor activation of ErbB-3 and ErbB-4 is cell specific and displays a differential requirement for ErbB-2

    Mol. Cell. Biol.

    (1995)
  • Cited by (0)

    View full text