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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.