title: Transautocrine signaling by membrane neuregulins requires cell surface targeting, which is controlled by multiple domains.
abstract: The neuregulins (NRGs) play important roles in animal development and homeostasis, and their deregulation has been linked to diseases such as cancer and schizophrenia. The NRGs belong to the epidermal growth factor (EGF) family of transmembrane growth factors. Although NRGs may be synthesized as transmembrane proteins (the pro-NRGs), some of them lack an N-terminal signal sequence, raising the question of how these pro-NRGs are directed to the plasma membrane. Here we have explored the domains of pro-NRGs that are required for their membrane anchoring, cell surface exposure, and biological activity. We show that an internal hydrophobic region acts as a membrane-anchoring domain, but other regions of pro-NRG are required for proper sorting to the plasma membrane. Using mutants that are located in different subcellular compartments, we show that only plasma membrane-exposed pro-NRG is biologically active. At this location, the pro-NRGs may act as transautocrine molecules (i.e. as membrane factors able to activate receptors present in cells that are in physical contact with the pro-NRG-producing cells (in trans) or capable of activating receptors present in the pro-NRG-producing cells (in cis)).
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer-Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Salamanca 37007, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Montero
authors.forename: Ruth
authors.initials: R
authors.lastname: Rodríguez-Barrueco
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
mesh_terms: D019898:Autocrine Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020880:Neuregulins / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000502:physiology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D020880:Neuregulins; D021382:Protein Sorting Signals