Regular articleNeuregulins: functions, forms, and signaling strategies
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
References (179)
- et al.
Isolation of the neu/HER-2 stimulatory liganda 44 kd glycoprotein that induces differentiation of mammary tumor cells
Cell
(1992) - et al.
Neu differentiation factora transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit
Cell
(1992) - et al.
Purification of multiple forms of glial growth factor
J. Biol. Chem.
(1993) - et al.
Binding specificities and affinities of egf domains for ErbB receptors
FEBS Lett.
(1999) - et al.
Neuregulin and ErbB receptor signaling pathways in the nervous system
Curr. Opin. Neurobiol.
(2001) - et al.
Differential signaling by the epidermal growth factor-like growth factors neuregulin-1 and neuregulin-2
J. Biol. Chem.
(1998) - et al.
Ligand discrimination in signaling through an ErbB4 receptor homodimer
J. Biol. Chem.
(2000) - et al.
Neuregulins and neuregulin receptors in neural development
Curr. Opin. Neurobiol.
(1997) - et al.
Neuregulins and their receptorsa versatile signaling module in organogenesis and oncogenesis
Neuron
(1997) - et al.
Targeting transcription to the neuromuscular synapse
Neuron
(2001)
Schwann cells and their precursors emerge as major regulators of nerve development
Trends Neurosci.
Schwann cells as regulators of nerve development
J. Physiol. Paris
Neuregulin 1 and susceptibility to schizophrenia
Am. J. Hum. Genet.
Sensory and motor neuron-derived factor—a novel heregulin variant highly expressed in sensory and motor neurons
J. Biol. Chem.
Heregulin, but not ErbB2 or ErbB3, heterozygous mutant mice exhibit hyperactivity in multiple behavioral tasks
Behav. Brain Res.
Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses
Neuron
Patterning of muscle acetylcholine receptor gene expression in the absence of motor innervation
Neuron
Transmembrane neuregulins interact with LIM kinase 1, a cytoplasmic protein kinase implicated in development of visuospatial cognition
J. Biol. Chem.
Neuregulin and erbB receptors play a critical role in neuronal migration
Neuron
A cysteine-rich isoform of neuregulin controls the level of expression of neuronal nicotinic receptor channels during synaptogenesis
Neuron
The N-terminal region of neuregulin isoforms determines the accumulation of cell-surface and released neuregulin ectodomain
J. Biol. Chem.
Differential expression of ARIA isoforms in the rat brain
Neuron
Sensory and motor neuron-derived factor is a transmembrane heregulin that is expressed on the plasma membrane with the active domain exposed to the extracellular environment
J. Biol. Chem.
Protein translocationtunnel vision
Cell
Forced transmembrane orientation of hydrophilic polypeptide segments in multispanning membrane proteins
Mol. Cell.
Release of the neuregulin functional polypeptide requires its cytoplasmic tail
J. Biol. Chem.
A role for a PDZ protein in the early secretory pathway for the targeting of proTGF-alpha to the cell surface
Mol. Cell.
Identification of a region within the ErbB2/HER2 intracellular domain that is necessary for ligand-independent association
J. Biol. Chem.
Trastuzumab cardiotoxicitySpeculations regarding pathophysiology and targets for further study
Semin. Oncol.
Cardiotoxicity in signal transduction therapeuticserbB2 antibodies and the heart
Semin. Oncol.
Neuregulins promote survival and growth of cardiac myocytes. Persistence of erbb2 and erbb4 expression in neonatal and adult ventricular myocytes
J. Biol. Chem.
Neuregulin expression in PNS neuronsisoforms and regulation by target interactions
Mol. Cell. Neurosci.
Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses
Neuron
Untangling the ErbB signaling network
Nat. Rev. Mol. Cell. Biol.
Identification of heregulin, a specific activator of p185erbB2
Science
Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system
Nature
ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family
Cell
Characterization of a neuregulin-related gene, don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus
Mol. Cell. Biol.
Neuregulin-2, a new ligand of erbB3/erbB4-receptor tyrosine kinases
Nature
Ligands for erbB-family receptors encoded by a neuregulin-like gene
Nature
A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4
J. Biochem. (Tokyo)
Neuregulin-3 (NRG3)a novel neural tissue-enriched protein that binds and activates ErbB4
Proc. Natl. Acad. Sci. USA
Neuregulin-4a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase
Oncogene
Neuregulin isoforms exhibit distinct patterns of ErbB family receptor activation
Oncogene
ErbB signaling regulates lineage determination of developing pancreatic islet cells in embryonic organ culture
Endocrinology
ARIA—a neuromuscular junction neuregulin
Annu. Rev. Neurosci.
Role of neuregulins in glial cell development
Glia
Neuregulin, a factor with many functions in the life of a schwann cell
Bioessays
Neuronal survivalearly dependence on Schwann cells
Curr. Biol.
The formation of neuromuscular synapses
Genes Dev.
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