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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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Circulation 102, 272-274
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E. J. Weinstein and P. Leder (2000)
Cancer Res. 60, 3856-3861
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J Natl Cancer Inst 92, 622-628
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N. V. Patel, M. J. Acarregui, J. M. Snyder, J. M. Klein, M. X. Sliwkowski, and J. A. Kern (2000)
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E. Levine, A. S. Cupp, L. Miyashiro, and M. K. Skinner (2000)
Biol Reprod 62, 477-490
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H. I. Rieff, L. T. Raetzman, D. W. Sapp, H. H. Yeh, R. E. Siegel, and G. Corfas (1999)
J. Neurosci. 19, 10757-10766
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Analysis of heregulin symmetry by weighted evolutionary tracing.
R. Landgraf, D. Fischer, and D. Eisenberg (1999)
Protein Eng. Des. Sel. 12, 943-951
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Regulation of Neuregulin-Mediated Acetylcholine Receptor Synthesis by Protein Tyrosine Phosphatase SHP2.
M. Tanowitz, J. Si, D.-H. Yu, G.-S. Feng, and L. Mei (1999)
J. Neurosci. 19, 9426-9435
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J. Si, Q. Wang, and L. Mei (1999)
J. Neurosci. 19, 8498-8508
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Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development.
M. T. Woldeyesus, S. Britsch, D. Riethmacher, L. Xu, E. Sonnenberg-Riethmacher, F. Abou-Rebyeh, R. Harvey, P. Caroni, and C. Birchmeier (1999)
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J. Biol. Chem. 274, 26407-26415
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K. M. W. Ignatoski, A. J. LaPointe, E. H. Radany, and S. P. Ethier (1999)
Endocrinology 140, 3615-3622
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Neuregulin in Cardiac Hypertrophy in Rats With Aortic Stenosis : Differential Expression of erbB2 and erbB4 Receptors.
S. Rohrbach, X. Yan, E. O. Weinberg, F. Hasan, J. Bartunek, M. A. Marchionni, and B. H. Lorell (1999)
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Heregulins or Neu Differentiation Factors and the Interactions between Peritubular Myoid Cells and Sertoli Cells.
E. Hoeben, J. V. Swinnen, W. Heyns, and G. Verhoeven (1999)
Endocrinology 140, 2216-2223
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Heregulin {beta}1-activated Phosphatidylinositol 3-Kinase Enhances Aggregation of MCF-7 Breast Cancer Cells Independent of Extracellular Signal-regulated Kinase.
M. Tan, R. Grijalva, and D. Yu (1999)
Cancer Res. 59, 1620-1625
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ErbB-2 Amplification Inhibits Down-regulation and Induces Constitutive Activation of Both ErbB-2 and Epidermal Growth Factor Receptors.
R. Worthylake, L. K. Opresko, and H. S. Wiley (1999)
J. Biol. Chem. 274, 8865-8874
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Neu Differentiation Factor Stimulates Phosphorylation and Activation of the Sp1 Transcription Factor.
I. Alroy, L. Soussan, R. Seger, and Y. Yarden (1999)
Mol. Cell. Biol. 19, 1961-1972
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Failure of spinal cord oligodendrocyte development in mice lacking neuregulin.
T. Vartanian, G. Fischbach, and R. Miller (1999)
PNAS 96, 731-735
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    PDF »
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)
Development 126, 1997-2005
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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)
J. Biol. Chem. 273, 34335-34340
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Biological Response to ErbB Ligands in Nontransformed Cell Lines Correlates with a Specific Pattern of Receptor Expression.
S. Sundaresan, P. E. Roberts, K. L. King, M. X. Sliwkowski, and J. P. Mather (1998)
Endocrinology 139, 4756-4764
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Sensory and Motor Neuron-derived Factor Is a Transmembrane Heregulin That Is Expressed on the Plasma Membrane with the Active Domain Exposed to the Extracellular Environment.
A. Schroering and D. J. Carey (1998)
J. Biol. Chem. 273, 30643-30650
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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)
Mol. Cell. Biol. 18, 6245-6252
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Neu Differentiation Factor (NDF), a Dominant Oncogene, Causes Apoptosis In Vitro and In Vivo.
S. Grimm, E. J. Weinstein, I. M. Krane, and P. Leder (1998)
J. Exp. Med. 188, 1535-1539
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Differential Signaling by the Epidermal Growth Factor-like Growth Factors Neuregulin-1 and Neuregulin-2.
C. S. Crovello, C. Lai, L. C. Cantley, and K. L. Carraway III (1998)
J. Biol. Chem. 273, 26954-26961
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ErbB Tyrosine Kinases and the Two Neuregulin Families Constitute a Ligand-Receptor Network.
R. Pinkas-Kramarski, M. Shelly, B. C. Guarino, L. M. Wang, L. Lyass, I. Alroy, M. Alamandi, A. Kuo, J. D. Moyer, S. Lavi, et al. (1998)
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Synapse-specific and neuregulin-induced transcription require an Ets site that binds GABPalpha /GABPbeta.
L. Fromm and S. J. Burden (1998)
Genes & Dev. 12, 3074-3083
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Mutation of a Shc Binding Site Tyrosine Residue in ErbB3/HER3 Blocks Heregulin-dependent Activation of Mitogen-activated Protein Kinase.
U. Vijapurkar, K. Cheng, and J. G. Koland (1998)
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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