ErbB Tyrosine Kinases and the Two Neuregulin Families Constitute a Ligand-Receptor Network

Abstract

The recently isolated second family of neuregulins, NRG2, shares its primary receptors, ErbB-3 and ErbB-4, and induction of mammary cell differentiation with NRG1 isoforms, suggesting functional redundancy of the two growth factor families. To address this possibility, we analyzed receptor specificity of NRGs by using an engineered cellular system. The activity of isoform-specific but partly overlapping patterns of specificities that collectively activate all eight ligand-stimulatable ErbB dimers was revealed. Specifically, NRG2-␤, like NRG1-␣, emerges as a narrow-specificity ligand, whereas NRG2-␣ is a pan-ErbB ligand that binds with different affinities to all receptor combinations, including those containing ErbB-1, but excluding homodimers of ErbB-2. The latter protein, however, displayed cooperativity with the direct NRG receptors. Apparently, signaling by all NRGs is funneled through the mitogen-activated protein kinase (MAPK). However, the duration and potency of MAPK activation depend on the identity of the stimulatory ligand-receptor ternary complex. We conclude that the NRG-ErbB network represents a complex and nonredundant machinery developed for fine-tuning of signal transduction.One of the relatively simple systems of signal transduction by a polypeptide growth factor is the mechanism controlling vulva formation in the nematode Caenorhabditis elegans (reviewed in reference 33). The most ancient epidermal growth factor (EGF)-like ligand, Lin-3, which is expressed by the anchor cell, binds to the Let-23 transmembrane tyrosine kinase on the surface of the closely apposed vulva precursor cell. The latter is then directed to a vulval fate through a biochemical cascade that sequentially activates a small GTP binding protein and a series of protein kinases, culminating in the mitogen-activated protein kinase (MAPK). A remarkably expanded version of this signaling module exists in mammals (reviewed in reference 6). Four receptors, whose structures are homologous to Let-23, and a few dozen ligands, all sharing the three-loop structure of EGF, form an interactive system with a large potential for signal diversification. In addition to the multiplicity of components, the modern version of the module is characterized by diversity: one ErbB protein, ErbB-3, is devoid of tyrosine kinase activity (25), and another, ErbB-2, binds no known EGFlike factor with high affinity (28, 61). Likewise, the various ligands carry, in addition to the EGF-like motif, a variety of structural domains thought to allow interaction with extracellular components. For example, the heparin binding EGF-like factor includes a heparan sulfate binding moiety (26), and the Neu differentiation factor (NDF, also called neuregulin 1 [NRG1], or heregulin) carries an immunoglobulin (Ig) domain (27,37,63).A combination of in vitro experiments and gene targeting in mice implies that the mammalian ErbB module, like its invertebrate counterparts in worms and in flies (46), is involved with fate determination of several cell lineages. Thus, ErbB-1, and...

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