Regular articleErbB-4: mechanism of action and biology
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)
- et al.
A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester
J. Biol. Chem.
(1997) - et al.
Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor
J. Biol. Chem.
(1993) - et al.
ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all neu differentiation factor/heregulin isoforms
J. Biol. Chem.
(1994) - et al.
Epiregulin is a potent pan-ErbB ligand that preferentially activates heterodimeric receptor complexes
J. Biol. Chem.
(1998) - et al.
Activation of ErbB4 by the bifunctional epidermal growth factor family hormone epiregulin is regulated by ErbB2
J. Biol. Chem.
(1998) - et al.
A novel epidermal growth factor-like molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB-4 in MKN28 gastric cancer cells
Biochem. Biophys. Res. Commun.
(1999) - et al.
An anti-oncogenic role for decorin. Down-regulation of ErbB2 leads to growth suppression and cytodifferentiations of mammary carcinoma cells
J. Biol. Chem.
(2000) - et al.
Ligand discrimination in signaling through an ErbB4 receptor homodimer
J. Biol. Chem.
(2000) - et al.
Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2
J. Biol. Chem.
(1996) - et al.
Formation of a high affinity heregulin binding site using the soluble extracellular domains of ErbB2 with ErbB3 or ErbB4
FEBS Lett.
(1998)