A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor.
The ErbB family includes four homologous transmembrane tyrosine kinases. Whereas ErbB-1 binds to the epidermal growth factor (EGF), both ErbB-3 and ErbB-4 bind to the Neu differentiation factors (NDFs, or neuregulins), and ErbB-2, the most oncogenic family member, is an orphan receptor whose function is still unknown. Because previous lines of evidence indicated the existence of interreceptor interactions, we used ectopic expression of individual ErbB proteins and their combinations to analyze the details of receptor cross talks. We show that 8 of 10 possible homo-and heterodimeric complexes of ErbB proteins can be hierarchically induced by ligand binding. Although ErbB-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with ErbB-3. Selective receptor overexpression in human tumor cells appears to bias the hierarchical relationships. The ordered network is reflected in receptor transphosphorylation, ErbB-2-mediated enhancement of ligand affinities, and remarkable potentiation of mitogenesis by a coexpressed ErbB-2. The observed superior ability of ErbB-2 to form heterodimers, in conjunction with its uniquely high basal tyrosine kinase activity, may explain why ErbB-2 overexpression is associated with poor prognosis.
Tzahar
E
E
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Waterman
H
H
Chen
X
X
Levkowitz
G
G
Karunagaran
D
D
Lavi
S
S
Ratzkin
B J
BJ
Yarden
Y
Y
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009414:Nerve Growth Factors / Q000494:pharmacology; D020880:Neuregulins; D010766:Phosphorylation; D055503:Protein Multimerization; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology*; D011869:Radioligand Assay; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D014162:Transfection
D006023:Glycoproteins; D009414:Nerve Growth Factors; D020880:Neuregulins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D004247:DNA; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D013936:Thymidine