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)).