The N-terminal domains of neuregulin 1 confer signal attenuation.
Degradation of activated ERBB receptors is an important mechanism for signal attenuation. However, compared with epidermal growth factor (EGF) receptor, the ERBB2/ERBB3 signaling pair is considered to be attenuation-deficient. The ERBB2/ERBB3 ligands of the neuregulin family rely on an EGF-like domain for signaling and are generated from larger membrane-bound precursors. In contrast to EGF, which is processed to yield a 6-kDa peptide ligand, mature neuregulins retain a variety of segments N-terminal to the EGF-like domain. Here we evaluate the role of the N-terminal domain of neuregulin 1 in signaling and turnover of ERBB2/ERBB3. Our data suggest that whereas the EGF-like domain of neuregulin 1 is required and sufficient for the formation of active receptor heterodimers, the presence of the N-terminal Ig-like domain is required for efficient signal attenuation. This manifests itself for both ERBB2 and ERBB3 but is more pronounced and coupled directly to degradation for ERBB3. When stimulated with only the EGF-like domain, ERBB3 shows degradation rates comparable with constitutive turnover, but stimulation with full-length neuregulin 1 resulted in receptor degradation at rates that are comparable with activated EGF receptor. Most of the enhancement in down-regulation was maintained after replacing the Ig-like domain with a thioredoxin protein of comparable size but different amino acid composition, suggesting that the physical presence but not specific properties of the Ig-like domain are needed. This sequence-independent effect of the N-terminal domain correlates with an enhanced ability of full-size neuregulin 1 to disrupt higher order oligomers of the ERBB3 extracellular domains in vitro.
Warren
Carmen M
CM
Department of Medicine, , Molecular Biology Institute, UCLA, Los Angeles, California 90095-1678, USA.
Kani
Kian
K
Landgraf
Ralf
R
D045744:Cell Line, Tumor; D019281:Dimerization; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D020890:Neuregulin-1 / Q000737:chemistry* / Q000502:physiology*; D020880:Neuregulins / Q000737:chemistry; D010766:Phosphorylation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry
D008024:Ligands; D020890:Neuregulin-1; D020880:Neuregulins; D020033:Protein Isoforms; D014443:Tyrosine