Identification of Heregulin, a Specific Activator of p185erbB2

  title={Identification of Heregulin, a Specific Activator of p185erbB2},
  author={William Evan Holmes and Mark X. Sliwkowski and Robert W. Akita and William J. Henzel and James M. Lee and John W. Park and Daniel G. Yansura and Nasrin Abadi and Helga Raab and Gail D. Lewis and H. Michael Shepard and W. J. Kuang and William l. Wood and David Norman Van Goeddel and Richard Vandlen},
  pages={1205 - 1210}
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-α (HRG-α) 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… 
Role of heregulin in human cancer
  • M. Breuleux
  • Biology
    Cellular and Molecular Life Sciences
  • 2007
Abstract.Heregulin (HRG) is a soluble secreted growth factor, which, upon binding and activation of ErbB3 and ErbB4 transmembrane receptor tyrosine kinases, is involved in cell proliferation,
Heregulin induces tyrosine phosphorylation of HER4/p180erbB4
Findings suggest that activation of the HER4 receptor is involved in signal transduction by heregulin, a specific ligand for HER4 that fails to induce phosphorylation of HER2 in the absence of HER4.
HER4 Expression Correlates with Cytotoxicity Directed by a Heregulin-Toxin Fusion Protein (*)
HAR-TX β2 was able to bind to and signal via tyrosine phosphorylation in cell lines that co-express HER2 and HER3 in the absence of HER4 without inducing cytotoxicity, suggesting it may prove to be a useful reagent for the targeting and elimination of Her4-positive tumor cells.
HER4 Receptor Activation and Phosphorylation of Shc Proteins by Recombinant Heregulin-Fc Fusion Proteins (*)
After thrombin protease cleavage of rHRGs-T-Fc, their EGF-like domains were purified and shown to stimulate protein phosphorylation in HER4-expressing cells, suggesting a role for these adaptor molecules in HRG-mediated signaling.
The Transmembrane Heregulin Precursor Is Functionally Active*
It is demonstrated that transmembrane heregulin is functionally active and suggested it is capable of playing a role in cell-cell communication and subsequent signal transduction in vivo.
Heregulins Implicated in Cellular Functions Other Than Receptor Activation
Observations strongly support the notion that HRG1 splice variants have multifunctional properties, including previously unknown regulatory functions within the nucleus that are different from the activation of ErbB receptor signaling.
Recombinant heregulin-Pseudomonas exotoxin fusion proteins: interactions with the heregulin receptors and antitumor activity in vivo.
  • D. Yang, C. Kuan, M. Lippman
  • Biology
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 1998
There is therapeutic potential of HRG-PE toxins in the therapy of cancers overexpressing the ErbB-4 or ErBB-2 plus Erb B-3 receptors, as well as other members of the type I receptor tyrosine kinase family.
Expression of messenger RNA for amphiregulin, heregulin, and cripto-1, three new members of the epidermal growth factor family, in human breast carcinomas
There was no significant association between AR, HRG, and CR-1 expression and nodal status, EGF receptor, or c-erbB-2 protooncogene expression in these tumors, however, a significant associationBetween AR expression and estrogen receptor positivity was observed.
Roles for neuregulins in human cancer
The analysis of ligand expression and/or activated receptors in tumor samples may broaden the group of patients that can benefit from targeted therapies.
A truncated intracellular HER2/neu receptor produced by alternative RNA processing affects growth of human carcinoma cells
Alternative processing of the HER2 transcript is demonstrated and a potentially important growth regulatory role for intracellularly sequestered HER2 ECD in HER2-amplified human tumors is implicate.


Experimental approaches to hypothetical hormones: detection of a candidate ligand of the neu protooncogene.
  • Y. Yarden, R. Weinberg
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1989
The following lines of evidence collectively imply that a candidate ligand of the neu-encoded oncoprotein is secreted by ras-transformed fibroblasts: medium conditioned by rAS transformants is able to induce down-modulation of the Neu oncogene p185 and to activate its intrinsic tyrosine kinase activity in vitro.
Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2.
Evidence described here suggests that gp30 is a ligand for p185erbB2, a 185-kilodalton transmembrane protein whose sequence is similar to the epidermal growth factor receptor (EGFR).
Characterization of a neu/c-erbB-2 protein-specific activating factor.
A neu protein-specific activating factor (NAF) was partially purified from medium conditioned by the transformed human T-cell line ATL-2 and was able to stimulate the tyrosine-specific kinase activity of the neuprotein (p185neu), induce dimerization and internalization, and increase the growth of cells bearing the neU protein.
Characterization of an anti-p185HER2 monoclonal antibody that stimulates receptor function and inhibits tumor cell growth.
The data suggest that 4D5 is a partial or weak agonist and thus may inhibit cell proliferation by mimicking ligand-like receptor downregulation as well as downregulating this signalling pathway since the intracellular levels of InsP and sn-1,2-DAG decreased by 30 to 40%.
p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor
It is shown that a monoclonal antibody directed against the extracellular domain of p185HER2 specifically inhibits the growth of breast tumor-derived cell lines overexpressing the HER2/c-erbB-2 gene product and prevents HER2-transformed NIH 3T3 cells from forming colonies in soft agar.
The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity.
Human placenta and ovaries were found to express significant amounts of the 1.4-kilobase AR transcript, implicating AR in the regulation of normal cell growth, and the gene was localized to chromosomal region 4q13-4q21, a common breakpoint for acute lymphoblastic leukemia.
Biochemical analysis of the ligand for the neu oncogenic receptor.
Biochemical analyses of the neu stimulatory activity indicate that the ligand is a 35-kDa glycoprotein that is heat stable but sensitive to reduction, and the presented biochemical characteristics of the factor are expected to enable a completely purified factor with which to explore these possibilities.
p185HER2 signal transduction in breast cancer cells.
Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells.
In experiments designed to assess the role of the HER2 gene in oncogenesis, overexpression of unaltered HER2 coding sequences in NIH 3T3 cells resulted in cellular transformation and tumorigenesis.