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Science 22 May 1992:
Vol. 256. no. 5060, pp. 1205 - 1210
DOI: 10.1126/science.256.5060.1205
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Articles

Identification of Heregulin, a Specific Activator of p185erbB2

William E. Holmes 1, Mark X. Sliwkowski 1, Robert W. Akita 1, William J. Henzel 1, James Lee 1, John W. Park 1, Daniel Yansura 1, Nasrin Abadi 1, Helga Raab 1, Gail D. Lewis 1, H. Michael Shepard 1, Wun-Jing Kuang 1, William l. Wood 1, David V. Goeddel 1, and Richard L. Vandlen 1

1 Departments of Protein Chemistry, Molecular Biology and Cell Biology, Genentech, Inc., South San Francisco, CA 94080

The proto-oncogene designated erbB2 or HER2 encodes a 185-kilodalton transmembrane tyrosine kinase (p185erbB2), whose overexpression has been correlated with a poor prognosis in several human malignancies. A 45-kilodalton protein heregulin-agr (HRG-agr) that specifically induced phosphorylation of p185erbB2 was purified from the conditioned medium of a human breast tumor cell line. Several complementary DNA clones encoding related HRGs were identified, all of which are similar to proteins in the epidermal growth factor family. Scatchard analysis of the binding of recombinant HRG to a breast tumor cell line expressing p185erbB2 showed a single high affinity binding site [dissociation constant (Kd) = 105 ± 15 picomolar]. Heregulin transcripts were identified in several normal tissues and cancer cell lines. The HRGs may represent the natural ligands for p185erbB2.


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I. Alroy, L. Soussan, R. Seger, and Y. Yarden (1999)
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Failure of spinal cord oligodendrocyte development in mice lacking neuregulin.
T. Vartanian, G. Fischbach, and R. Miller (1999)
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A Discrete Three-amino Acid Segment (LVI) at the C-terminal End of Kinase-impaired ErbB3 Is Required for Transactivation of ErbB2.
G. Schaefer, R. W. Akita, and M. X. Sliwkowski (1999)
J. Biol. Chem. 274, 859-866
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Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy.
P Nagy, A Jenei, A. Kirsch, J Szollosi, S Damjanovich, and T. Jovin (1999)
J. Cell Sci. 112, 1733-1741
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Heparin-binding EGF-like growth factor interacts with mouse blastocysts independently of ErbB1: a possible role for heparan sulfate proteoglycans and ErbB4 in blastocyst implantation.
B. Paria, K Elenius, M Klagsbrun, and S. Dey (1999)
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Release of the Neuregulin Functional Polypeptide Requires Its Cytoplasmic Tail.
X. Liu, H. Hwang, L. Cao, D. Wen, N. Liu, R. M. Graham, and M. Zhou (1998)
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S. Sundaresan, P. E. Roberts, K. L. King, M. X. Sliwkowski, and J. P. Mather (1998)
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Synergistic Regulation of Schwann Cell Proliferation by Heregulin and Forskolin.
M. Rahmatullah, A. Schroering, K. Rothblum, R. C. Stahl, B. Urban, and D. J. Carey (1998)
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J. Biol. Chem. 273, 20996-21002
   Abstract »    Full Text »    PDF »
Transmembrane Neuregulins Interact with LIM Kinase 1, a Cytoplasmic Protein Kinase Implicated in Development of Visuospatial Cognition.
J. Y. Wang, K. E. Frenzel, D. Wen, and D. L. Falls (1998)
J. Biol. Chem. 273, 20525-20534
   Abstract »    Full Text »    PDF »
The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system.
S. Britsch, L. Li, S. Kirchhoff, F. Theuring, V. Brinkmann, C. Birchmeier, and D. Riethmacher (1998)
Genes & Dev. 12, 1825-1836
   Abstract »    Full Text »
Binding Interaction of the Heregulinbeta egf Domain with ErbB3 and ErbB4 Receptors Assessed by Alanine Scanning Mutagenesis.
J. T. Jones, M. D. Ballinger, P. I. Pisacane, J. A. Lofgren, V. D. Fitzpatrick, W. J. Fairbrother, J. A. Wells, and M. X. Sliwkowski (1998)
J. Biol. Chem. 273, 11667-11674
   Abstract »    Full Text »    PDF »
Selection of Heregulin Variants Having Higher Affinity for the ErbB3 Receptor by Monovalent Phage Display.
M. D. Ballinger, J. T. Jones, J. A. Lofgren, W. J. Fairbrother, R. W. Akita, M. X. Sliwkowski, and J. A. Wells (1998)
J. Biol. Chem. 273, 11675-11684
   Abstract »    Full Text »    PDF »
Analysis of Grb7 Recruitment by Heregulin-activated erbB Receptors Reveals a Novel Target Selectivity for erbB3.
R. J. Fiddes, D. H. Campbell, P. W. Janes, S. P. Sivertsen, H. Sasaki, C. Wallasch, and R. J. Daly (1998)
J. Biol. Chem. 273, 7717-7724
   Abstract »    Full Text »    PDF »
Activity-dependent regulation of Neu differentiation factor/neuregulin expression in rat brain.
R. Eilam, R. Pinkas-Kramarski, B. J. Ratzkin, M. Segal, and Y. Yarden (1998)
PNAS 95, 1888-1893
   Abstract »    Full Text »    PDF »
In Vivo Analysis of Argos Structure-Function. SEQUENCE REQUIREMENTS FOR INHIBITION OF THE DROSOPHILA EPIDERMAL GROWTH FACTOR RECEPTOR.
R. Howes, J. D. Wasserman, and M. Freeman (1998)
J. Biol. Chem. 273, 4275-4281
   Abstract »    Full Text »    PDF »
The formation of neuromuscular synapses.
S. J. Burden (1998)
Genes & Dev. 12, 133-148
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Selective disruption of neuregulin-1 function in vertebrate embryos using ribozyme-tRNA transgenes.
J. Zhao and G Lemke (1998)
Development 125, 1899-1907
   Abstract »    PDF »
Cross-talk between Phorbol Ester-mediated Signaling and Tyrosine Kinase Proto-oncogenes. I. ACTIVATION OF PROTEIN KINASE C STIMULATES TYROSINE PHOSPHORYLATION AND ACTIVATION OF ErbB2 AND ErbB3.
R. Emkey and C. R. Kahn (1997)
J. Biol. Chem. 272, 31172-31181
   Abstract »    Full Text »    PDF »
Hepatic Expression of ErbB3 Is Repressed by Insulin in a Pathway Sensitive to PI-3 Kinase Inhibitors.
R. S. Carver, P. M. Mathew, and W. E. Russell (1997)
Endocrinology 138, 5195-5201
   Abstract »    Full Text »    PDF »
A Novel Juxtamembrane Domain Isoform of HER4/ErbB4. ISOFORM-SPECIFIC TISSUE DISTRIBUTION AND DIFFERENTIAL PROCESSING IN RESPONSE TO PHORBOL ESTER.
K. Elenius, G. Corfas, S. Paul, C. J. Choi, C. Rio, G. D. Plowman, and M. Klagsbrun (1997)
J. Biol. Chem. 272, 26761-26768
   Abstract »    Full Text »    PDF »
Neuregulin-3 (NRG3): A novel neural tissue-enriched protein that binds and activates ErbB4.
D. Zhang, M. X. Sliwkowski, M. Mark, G. Frantz, R. Akita, Y. Sun, K. Hillan, C. Crowley, J. Brush, and P. J. Godowski (1997)
PNAS 94, 9562-9567
   Abstract »    Full Text »    PDF »
Glial Growth Factor Rescues Schwann Cells of Mechanoreceptors from Denervation-Induced Apoptosis.
D. M. Kopp, J. T. Trachtenberg, and W. J. Thompson (1997)
J. Neurosci. 17, 6697-6706
   Abstract »    Full Text »    PDF »
Mitosis-specific Negative Regulation of Epidermal Growth Factor Receptor, Triggered by a Decrease in Ligand Binding and Dimerization, Can Be Overcome by Overexpression of Receptor.
N. Kiyokawa, E. K. Lee, D. Karunagaran, S.-Y. Lin, and M.-C. Hung (1997)
J. Biol. Chem. 272, 18656-18665
   Abstract »    Full Text »    PDF »
Follicle-Stimulating Hormone Induces Terminal Differentiation in a Predifferentiated Rat Granulosa Cell Line (ROG).
R. Li, D. M. Phillips, A. Moore, and J. P. Mather (1997)
Endocrinology 138, 2648-2657
   Abstract »    Full Text »    PDF »
Neuregulins stimulate the functional expression of Ca2+-activated K+ channels in developing chicken parasympathetic neurons.
P. Subramony and S. E. Dryer (1997)
PNAS 94, 5934-5938
   Abstract »    Full Text »    PDF »


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