Extracellular domains drive homo- but not hetero-dimerization of erbB receptors.
Many different growth factor ligands, including epidermal growth factor (EGF) and the neuregulins (NRGs), regulate members of the erbB/HER family of receptor tyrosine kinases. These growth factors induce erbB receptor oligomerization, and their biological specificity is thought to be defined by the combination of homo- and hetero-oligomers that they stabilize upon binding. One model proposed for ligand-induced erbB receptor hetero-oligomerization involves simple heterodimerization; another suggests that higher order hetero-oligomers are 'nucleated' by ligand-induced homodimers. To distinguish between these possibilities, we compared the abilities of EGF and NRG1-beta1 to induce homo- and hetero-oligomerization of purified erbB receptor extracellular domains. EGF and NRG1-beta1 induced efficient homo-oligomerization of the erbB1 and erbB4 extracellular domains, respectively. In contrast, ligand-induced erbB receptor extracellular domain hetero-oligomers did not form (except for s-erbB2-s-erbB4 hetero-oligomers). Our findings argue that erbB receptor extracellular domains do not recapitulate most heteromeric interactions of the erbB receptors, yet reproduce their ligand-induced homo-oligomerization properties very well. This suggests that mechanisms for homo- and hetero-oligomerization of erbB receptors are different, and contradicts the simple heterodimerization hypothesis prevailing in the literature.
Ferguson
K M
KM
Department of Biochemistry & Biophysics and Johnson Research Foundation, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6059, USA.
Darling
P J
PJ
Mohan
M J
MJ
Macatee
T L
TL
Lemmon
M A
MA
D019281:Dimerization; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D018739:Oncogene Proteins v-erbB / Q000378:metabolism*; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
D004815:Epidermal Growth Factor; D018739:Oncogene Proteins v-erbB; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins