The deaf and the dumb: the biology of ErbB-2 and ErbB-3

doi:10.1016/S0014-4827(02)00101-5

Experimental Cell Research

Volume 284, Issue 1, 10 March 2003, Pages 54-65

https://doi.org/10.1016/S0014-4827(02)00101-5 Get rights and content

Abstract

ErbB-2 (also called HER2/neu) and ErbB-3 are closely related to the epidermal growth factor receptor (EGFR/ErbB-1), but unlike EGFR, ErbB-2 is a ligandless receptor, whereas ErbB-3 lacks tyrosine kinase activity. Hence, both ErbB-2 and ErbB-3 are active only in the context of ErbB heterodimers, and ErbB-2 · ErbB-3 heterodimers, which are driven by neuregulin ligands, are the most prevalent and potent complexes. These stringently controlled heterodimers are repeatedly employed throughout embryonic development and dictate the establishment of several cell lineages through mesenchyme-epithelial inductive processes and the interactions of neurons with muscle, glia, and Schwann cells. Likewise, the potent combination of signaling pathways engaged by the heterodimers drives an aggressive phenotype of tumors of secretory epithelia, including breast and lung cancers. This review highlights recent structural insights into the mechanism of ligand-induced heterodimer formation, and concentrates on signaling pathways employed by ErbB-2 and ErbB-3 in normal and in malignant cells.

Introduction

The ErbB-2 · ErbB-3 heterodimer constitutes the pinnacle of ErbB receptor evolution, demonstrating the capacity of evolution to form an extremely potent signaling module from a pair of singly inactive individual proteins. The diversification of the ErbB family during evolution, from one receptor/ligand in worms, through one receptor/multiple ligands in flies, to four receptors and multiple ligands in mammals, has created a network capable of precise signaling in a widely divergent fashion [1]. Thus, through utilization of defined receptor pairs, activated by specific ligands, a graded signaling potency can be obtained, leading to a precise cellular outcome. An additional level of signaling diversity is obtained through differential activation of distinct signaling molecules downstream of each receptor. The capacity to form precise signaling is best exemplified by the ErbB-2 · ErbB-3 dimer. ErbB-3 is an impaired kinase due to substitutions in critical residues in its catalytic domain [2], and thus can signal only in the context of a receptor heterodimer. In addition, it is now clear that ErbB-2 is devoid of an activating ligand [3] and can act only in the context of a heterodimer with a ligand-bound receptor. In stark contrast to their apparent disabilities, this receptor pair forms the most potent signaling module of the ErbB-receptor family in terms of cell growth and transformation [4], [5]. That the most potent signaling module is formed by partners that are incapable of productively signaling in isolation suggests that evolutionary forces formed these mechanisms as a measure to tightly control the output of the network. As will be described below, the basis for the potency of signaling by the ligand-activated ErbB-2 · ErbB-3 heterodimer lies in the fact that this dimer has the capacity to signal very potently, both through the Ras-Erk pathway for proliferation, and through the phosphatidylinositol-3′-kinase (PI3K)-Akt pathway for survival. In addition, this receptor dimer evades downregulation mechanisms, leading to prolonged signaling [6], [7].

Section snippets

ErbB-2 and ErbB-3 as determinants of cell lineages

Organ morphogenesis is controlled, at least in part, by multiple polypeptide factors that transmit signals between neighboring cells. The ErbB-receptor family plays a pivotal role in cell lineage determination in a variety of tissues, including mesenchyme-epithelial inductive processes in epithelial organs (reviewed by Burden and Yarden [8]). ErbB-2 and ErbB-3, as well as ErbB-1, are expressed in most epithelial cell layers, and mesenchymal cells are a rich source of ErbB-ligands, both

Formation of ErbB-2 · ErbB-3 heterodimers: structural insights

While it is clear that dimerization of ErbB proteins is crucial for signaling (reviewed by Heldin and Ostman [31]), the underlying mechanism remained elusive until very recently. Three published structures of the extracellular domains of ErbB family receptors [32], [33], [34] have recently provided a framework for understanding the large amount of data that have accumulated over the years with respect to ligand binding and receptor activation. ErbB receptors share a high degree of primary

Signal transduction by erbb-2 · erbb-3 dimers

Cancers do not necessarily arise as a linear result of an increased rate of cellular proliferation, but rather the balance between cell division and apoptosis is the crucial factor [55]. This principle is demonstrated by the oncogenic potential of the ErbB-2 · ErbB-3 dimer; this receptor signals through both the mitogen-activated protein kinase (MAPK) pathway, which drives cell proliferation and additional processes, and through the PI3K/Akt pathway, which primarily drives cellular survival and

Clinical implications of the cooperation between ErbB-2 and ErbB-3

Several lines of evidence derived from animal models and in vitro systems imply that ErbB-1 can transform naive cells only when one of its ligands, primarily TGFα, is available [50], [108]. Consistent with this notion, analyses of human tumors from gastric, breast, pancreatic, and other origins indicated that autocrine loops underlie poor prognosis of the relevant ErbB-1-overexpressing tumors (reviewed by Salomon et al. [109]). Another critical partner of ErbB-1 is ErbB-2, as their coexpression

Perspectives

Peaking in the recent months, the past 15 years have been highly instructive as to the basic principles underlying the action of ErbB receptors, and in describing their relevance to tumorigenesis, thereby opening windows for therapeutic opportunities. Thus, the basic principle of receptor heterodimerization has taught us that the context in which a receptor functions is crucial for predicting the resulting signal. This context is beginning to be extended to the interaction of the ErbBs with

Acknowledgements

We thank Sarah Bacus, Jorma Isola, and Mark Sliwkowski for insightful discussions. Our laboratory is supported by grants from the National Cancer Institute, the U.S. Army, the European Commission, and the Israel Academy of Sciences and Humanities.

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Regular articleThe deaf and the dumb: the biology of ErbB-2 and ErbB-3

Abstract

Introduction

Section snippets

ErbB-2 and ErbB-3 as determinants of cell lineages

Formation of ErbB-2 · ErbB-3 heterodimers: structural insights

Signal transduction by erbb-2 · erbb-3 dimers

Clinical implications of the cooperation between ErbB-2 and ErbB-3

Perspectives

Acknowledgements

J. Biol. Chem.

Neuron

Neuron

Curr. Biol.

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

Cell

J. Biol. Chem.

Cell

FEBS Lett.

Mol. Cell.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell. Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Curr. Opin. Gen. Dev.

Cell

Curr. Biol.

Cell

J. Biol. Chem.

Untangling the ErbB signalling network

Nat. Rev. Mol. Cell. Biol.

Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity

Proc. Natl. Acad. Sci. USA

The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors

Proc. Natl. Acad. Sci. USA

Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions

EMBO J.

Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3

EMBO J.

The C-terminus of the kinase-defective neuregulin receptor ErbB-3 confers mitogenic superiority and dictates endocytic routing

EMBO J.

Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene

Science

Expression of the c-erbB-3 protein in normal human adult and fetal tissues

Oncogene

Neuregulin, a factor with many functions in the life of a schwann cell

Bioessays

Requirement for neuregulin receptor erbB2 in neural and cardiac development

Nature

Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor

Nature

Multiple essential functions of neuregulin in development

Nature

The catalytic activity of the ErbB-2 receptor tyrosine kinase is essential for embryonic development

Mol. Cell. Biol.

ErbB3 is required for normal cerebellar and cardiac developmenta comparison with ErbB2-and heregulin-deficient mice

Development

Severe neuropathies in mice with targeted mutations in the ErbB3 receptor

Nature

ErbB2 is essential in the prevention of dilated cardiomyopathy

Nat. Med.

Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy

Proc. Natl. Acad. Sci. USA

Role of neuregulins in glial cell development

Glia

The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system

Genes Dev.

The erbB2 gene is required for the development of terminally differentiated spinal cord oligodendrocytes

J. Cell Biol.

Axonal interactions regulate Schwann cell apoptosis in developing peripheral nerveneuregulin receptors and the role of neureguins

Regular article
The deaf and the dumb: the biology of ErbB-2 and ErbB-3