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Molecular and Cellular Biology, October 1998, p. 6090-6101, Vol. 18, No. 10
Departments of Molecular Cell
Biology,1
Structural
Biology,5 and
Membrane Research and
Recognition,7 The Weizmann Institute of
Science, Rehovot 76100, Israel;
Pfizer Central Research,
Groton, Connecticut 063402;
The
National Cancer Institute, Bethesda, Maryland
208923;
Advanced Cellular Diagnostics,
Inc., Elmhurst Illinois 601264; and
Amgen Center, Thousand Oaks, California 913206
Received 21 August 1997/Returned for modification 21 October
1997/Accepted 7 July 1998
The recently isolated second family of neuregulins, NRG2, shares
its primary receptors, ErbB-3 and ErbB-4, and induction of mammary cell
differentiation with NRG1 isoforms, suggesting functional redundancy of
the two growth factor families. To address this possibility, we
analyzed receptor specificity of NRGs by using an engineered cellular
system. The activity of isoform-specific but partly overlapping
patterns of specificities that collectively activate all eight
ligand-stimulatable ErbB dimers was revealed. Specifically, NRG2-
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
ErbB Tyrosine Kinases and the Two Neuregulin
Families Constitute a Ligand-Receptor Network
,
like NRG1-
, emerges as a narrow-specificity ligand, whereas NRG2-
is a pan-ErbB ligand that binds with different affinities to all
receptor combinations, including those containing ErbB-1, but excluding
homodimers of ErbB-2. The latter protein, however, displayed
cooperativity with the direct NRG receptors. Apparently, signaling by
all NRGs is funneled through the mitogen-activated protein kinase
(MAPK). However, the duration and potency of MAPK activation depend on
the identity of the stimulatory ligand-receptor ternary complex. We
conclude that the NRG-ErbB network represents a complex and
nonredundant machinery developed for fine-tuning of signal
transduction.
*
Corresponding author. Mailing address: Department of
Molecular Cell Biology, The Weizmann Institute of Science, Rehovot
76100, Israel. Phone: 972-8-9342866. Fax: 972-8-9344125. E-mail:
liyarden{at}wiccmail.weizmann.ac.il.
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