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Molecular and Cellular Biology, October 1998, p. 6090-6101, Vol. 18, No. 10
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

Ronit Pinkas-Kramarski,1 Maya Shelly,1 Bradley C. Guarino,2 Ling Mei Wang,3 Ljuba Lyass,4 Iris Alroy,1 Mauricio Alamandi,3 Angera Kuo,3 James D. Moyer,2 Sara Lavi,1 Miriam Eisenstein,5 Barry J. Ratzkin,6 Rony Seger,7 Sarah S. Bacus,4 Jacalyn H. Pierce,3 Glenn C. Andrews,2 and Yosef Yarden1,*

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-beta , like NRG1-alpha , emerges as a narrow-specificity ligand, whereas NRG2-alpha 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.

Molecular and Cellular Biology, October 1998, p. 6090-6101, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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