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Neuregulins: functions, forms, and signaling strategies

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Abstract

The neuregulins (NRGs) are cell-cell signaling proteins that are ligands for receptor tyrosine kinases of the ErbB family. The neuregulin family of genes has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins, and they are considered in this review only briefly. The NRG1 proteins play essential roles in the nervous system, heart, and breast. There is also evidence for involvement of NRG signaling in the development and function of several other organ systems, and in human disease, including the pathogenesis of schizophrenia and breast cancer. There are many NRG1 isoforms, raising the question “Why so many neuregulins?” Study of mice with targeted mutations (“knockout mice”) has demonstrated that isoforms differing in their N-terminal region or in their epidermal growth factor (EGF)-like domain differ in their in vivo functions. These differences in function might arise because of differences in expression pattern or might reflect differences in intrinsic biological characteristics. While differences in expression pattern certainly contribute to the observed differences in in vivo functions, there are also marked differences in intrinsic characteristics that may tailor isoforms for specific signaling requirements, a theme that will be emphasized in this review.

Section snippets

The discovery of neuregulins (NRGs); NRG family genes; the focus of this review

Neuregulins (NRGs) are signaling proteins that mediate cell-cell interactions in the nervous system, heart, breast, and other organ systems. “Forward” signaling by NRGs—i.e., signaling from a NRG-producing cell to a NRG-responsive cell—involves binding of NRG to the extracellular domain of the receptor tyrosine kinases ErbB3 or ErbB4, which leads to formation of ErbB homo- or heterodimers (often including ErbB2), which in turn activates intracellular signaling pathways leading to cellular

The NRG1 gene; NRG1 isoforms and nomenclature

An important recent advance is the sequencing and assembly of the entire human NRG1 gene (Fig. 1A, [34]). The gene is ≈1.4 megabases long (≈1/2000th of the genome); less than 0.3% of this span encodes protein. As a consequence of rich alternative splicing and multiple promoters, at least 15 different NRG isoforms are produced from the single NRG1 gene (Fig. 1B and C [17], [20]). The three structural characteristics we know to importantly differentiate isoforms with respect to in vivo functions

NRG1 signaling in health; isoforms differing in their N-terminal region or EGF-like domain differ in their in vivo functions

Without NRGs life is not possible. However, even I—a confirmed neuregulin fanatic—was surprised as I surveyed the literature in preparation for writing this review, at how pervasive NRG signaling appears to be (Table 1). While I will here introduce the in vivo functions of NRGs by describing the dramatic phenotypes of the knockouts, it must be emphasized that a number of other experimental approaches have made important contributions to our current understanding of NRG functions, and it seems

NRG1 signaling in disease: evidence for involvement in pathophysiology and potential therapeutic uses

The many functions of neuregulins revealed through knockout and other studies (Table 1, Table 2) attest to the importance of neuregulin signaling during development and in the adult. Are disorders of neuregulin signaling involved in the pathogenesis of disease, and what are the prospects for disease therapy based on modulating neuregulin signaling? Table 3 summarizes currently investigated pathological and therapeutic considerations with respect to NRG1. Here I will briefly describe only one:

Sometimes a kiss sent from a distance may be sufficient, but in other situations a kiss on the lips may be required: NRG1 paracrine signaling by shedding and secretion and NRG1 juxtacrine signaling

The ErbB family of receptors and their ligands has been described as a “signaling network” with an input layer comprised of ligands, receptors, and transactivators; a signal processing layer comprised of adapters, cascades, and transcription factors; and an output layer comprised of the biological consequences of ligand-ErbB interaction, such as stimulation of proliferation, inhibition of apoptosis, and differentiation ([1]; see also [[98], [99], [100]] and companion reviews in this issue). In

Paracrine signaling by Ig-NRGs

Paracrine signaling refers to short distance cell-cell communication mediated by diffusible signaling molecules. Communication mediated by such diffusible signals allows cells not in direct contact to “talk to” each other. Proteins that serve as “paracrine signals” are commonly synthesized as soluble proteins, which—following processing in the ER-Golgi system and transport—are released by secretion, the spilling out of the trafficking vesicle’s contents when it fuses with the cell’s plasma

Are CRD-NRGs (type III NRGs) specialized to serve as juxtacrine signals?

Initially it was assumed that like type I NRGs, the type III NRGs with a transmembrane domain C-terminal of the EGF-like domain (TMc-NRGs), such as III-β1a, would be single pass transmembrane proteins and that stalk cleavage of Type III NRGs would shed a bioactive ectodomain fragment that includes both the “cysteine-rich domain” (CRD) and the EGF-like domain. However, a direct test of this model in which type I and type III NRGs were expressed by transfection in fibroblastic cell lines [77]

Even for a kiss sent from a distance, the tingle can linger: prolongation of Ig-NRG’s effect by heparin

The retention of type III NRGs in the membrane of type III expressing cells may not only limit the range of signaling, but also effectively concentrate the signal by confining it to the two-dimensional plane of the membrane. There is recent evidence for an alternative strategy of signal enhancement employed by Ig-NRGs. Each of the protein purification schemes by which NRGs were initially isolated employed a step of heparin chromatography, and each purified an Ig-NRG. In retrospect this is not

A tale of the heart (and of paracrine signaling, Ig-NRGs, the NRG cytoplasmic tail, and NRG trafficking)

As noted above, mice genetically altered so that they produce no bioactive Ig-NRGs (Ig-NRG KOs) have the same cardiac phenotype as the pan-NRG KOs. Mice homozygous for NRG1 mutation that causes all transmembrane NRG1s (TMc-NRG1s) to have their tail truncated to a length of only three amino acids (NRG1ΔCT/ΔCT mice) also have the same cardiac phenotype ([44]; see Table 2). However mice that produce no bioactive CRD-NRGs have not been reported to have cardiac defects. What is the underlying cell

Conclusion

We certainly are just at the beginning of deciphering the functions of NRGs and the mechanisms by which the NRG signaling is shaped and modulated to achieve physiologically adaptive outcomes, but already it is clear the NRGs play critical roles in the functioning of a number of organ systems, both during embryonic development and postnatally. Evidence that aberrations in NRG signaling contribute to the pathology of diseases such as schizophrenia and multiple sclerosis lend additional urgency to

Acknowledgements

Preparation of this article was supported by a grant to D.L.F. from the National Institutes of Health (GM56337).

Note added in proof. A good entry point for access to the wealth of NRG isoform information freely available via the World Wide Web is LocusLink [170], [171] (http:www.ncbi.nlm.nih.gov/LocusLink/). To begin accessing the LocusLink neuregulin information, on the LocusLink home page enter “neuregulin” in the query box (without quotation marks), and then click “Go.” This will take you to

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